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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.	Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis. Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA. Introduction The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), such as golimumab (GLM), has transformed the treatment of rheumatoid arthritis (RA). GLM is a human monoclonal IgG antibody that binds to tumor necrosis factor-alpha (TNF-α) (1). GLM in combination with methotrexate (MTX) has shown efficacy and safety in phase III clinical trials (2-4). In Japan, the GO-FORTH (5) and GO-MONO (6) trials demonstrated the clinical efficacy and safety of GLM in combination with MTX and as monotherapy, respectively. Based on these data, the Japanese Pharmaceuticals and Medical Devices Agency approved GLM (50 and 100 mg) as the fourth anti-TNF-α antibody in 2011 (7); the 100 mg dose is only available in Japan (8). Sevedbom et al. performed a systematic review to determine the continuation rate of GLM (9). They identified 12 real-world studies; however, only 3 were original articles, whereas the remaining 9 were abstracts from academic conferences (10-12). There have been a few reports of the 100 mg GLM regimen in daily practice administered once every 4 weeks (8,11,13); these reports had follow-up periods of up to 52 weeks. Shono (13) compared the clinical safety and efficacy between a bio-naïve and bio-switch group and reported that the improvement in disease activity was similar between the groups at 24 weeks. Although the GO-FORWARD, GO-AFTER, GO-BEFORE, and GO-MONO studies were randomized controlled trials to show the efficacy and safety of GLM from 120 weeks to 5 years, they differed from studies in real clinical settings (2,14-16). The European League Against Rheumatism (EULAR) has recommended the short-term use of prednisolone (PSL) to control disease activity (17). Since a high dose of PSL has many adverse effects, reducing the dose is useful (18). MTX plays an important role in the treatment of RA, but it also has side effects (19), causing many patients to wish to taper or discontinue MTX therapy (20). Since the introduction of the treat-to-target strategy, patients have sought to achieve a high quality of life (QOL). The Japanese version of the health assessment questionnaire (J-HAQ) is an instrument for measuring the physical function and health-related QOL (21). Sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance” by the Asian Working Group for Sarcopenia in 2014, with a consensus update in 2019 (22). The diagnostic criterion of “low muscle strength” is defined as a grip power <28 kg for men and <18 kg for women. Sarcopenia enhances the fall burden, decreases healthy life expectancy, and increases healthcare costs (23,24). Previous reports on the prevalence of sarcopenia have varied; for example, a meta-analysis showed that the prevalence of sarcopenia in patients with RA was 15-32% (25), and Torii et al. reported a prevalence of 37.1% in Japanese patients (23). In addition, Ishikawa et al. reported that the handgrip power in Japanese patients with RA reflects the level of independence in activity of daily living (ADL), and the cut-off value for independent ADL was 136.5 mmHg (11.8 kgw) for women and 152.5 mmHg (13.5 kgw) for men (26). Only one report has described an improvement in the grip power following the use of bDMARDs, with the use of TNF inhibitors for more than one year being shown to improve the grip power in patients with RA (27). We hypothesized that improving the grip power can not only ameliorate inflammation in the upper extremities in patients with RA but also decrease sarcopenia and increase the healthy life expectancy. We hypothesized that the long-term use of GLM would be safe and effective in bio-naïve and bio-switch patients in real clinical practice and that the use of GLM would facilitate better disease control, reduce the PSL and MTX dosages, and improve the J-HAQ and grip power. Furthermore, we hypothesized that the grip power correlates with the J-HAQ score and Disease Activity Score (DAS) 28-ESR. Therefore, in the present study, we evaluated the effectiveness and drug continuation rate of long-term use of GLM in bDMARD-naïve and switch patients in clinical practice in order to determine the reason for discontinuation because of a lack of efficacy. Materials and Methods We retrospectively analyzed the data of patients with RA administered GLM at Niigata Rheumatic Center from October 2011 to March 2015. Sixty-five patients (58 women and 7 men) started GLM therapy during this period. All patients were followed up for more than 52 weeks. Data were collected in March 2016 and retrospectively analyzed (Table 1). The patients were divided into bDMARD “naïve” and “switch” groups based on their history of use. Table 1. Characteristics of Patients in the Naïve and Switch Groups. Total (n=65) Naïve (n=28) Switch (n=37) p value Female, n (%) 58 (89%) 25 (89%) 33 (89%) 0.990 Age, years 69 (61-74) 68 (60-71) 70 (60-76) 0.180 Disease duration of RA, years 9 (5-16) 10 (2-20) 9 (7-16) 0.418 Follow up period 134 (58-162) 127 (79-148) 142 (80-170) 0.310 Swollen joint count 3 (1-6) 3 (1-6) 2 (0-6) 0.414 Tender joint count 3 (1-6) 4 (1-8) 2 (1-5) 0.149 Patient’s global VAS score, mm 46 (23-59) 47 (25-60) 46 (21-59) 0.842 Doctor’s global VAS score, mm 35 (23-60) 40 (26-60) 35 (19-52) 0.524 ESR, mm/h 23 (12-50) 24 (10-49) 23 (14-50) 0.628 CRP, mg/dL 0.60 (0.10-2.10) 0.40 (0.1-1.8) 0.80 (0.10-2.55) 0.110 RF, IU/mL 47 (18-112) 73 (21-231) 43 (11-99) 0.040* RF, positive (%) 49 (75%) 26 (93%) 23 (62%) 0.003* ACPA, U/mL 88 (22-244) 117 (22-248) 67 (25-213) 0.367 ACPA, positive (%) 57 (87%) 26 (93%) 31 (84%) 0.172 MMP-3, ng/mL 128 (67-214) 93 (62-171) 142 (70-249) 0.161 DAS28-ESR 4.27 (3.35-5.19) 4.31 (3.52-5.25) 4.27 (3.19-4.89) 0.521 J-HAQ 0.40 (0.05-0.84) 0.25 (0.04-0.71) 0.48(0.21-0.88) 0.223 MTX use, n (%) 43 (66%) 22 (79%) 21 (57%) 0.066 Dose of MTX, mg/week 8.0 (0.0-10.0) 8.0 (6.0-10.0) 5.0 (0.0-8.5) 0.046* PSL use, n (%) 42(65%) 16 (57%) 26 (70%) 0.299 Dose of PSL, mg/day 3.0 (0.0-5.0) 2.3 (0.0-5.0) 3.0 (0.0-5.0) 0.299 Steinbrocker Stage (I, II, III, IV) 4:10:17:34 3:5:6:14 1:5:11:20 0.507 Steinbrocker Class (1, 2, 3, 4) 1:35:27:2 1:20:7:0 0:15:20:2 0.030* Initial dose of GLM (50 mg:100 mg) 38:27 24:4 14:23 <0.001** Number of patients with dose escalation, n (%) 20 (31%) 13 (46%) 7 (19%) 0.017* Number of patients who discontinued treatment, n (%) 17 (26%) 6 (21%) 11 (30%) 0.450 P value was calculated by comparing naïve and switch groups. A chi-square test was used for comparison of categorical data between the two groups. The Mann-Whitney U test was used to assess continuous variables of non-paired data. : p<0.05, : p<0.01. Median (range). RA: rheumatoid arthritis, VAS: visual analog scale, ESR: erythrocyte sedimentation rate, CRP: the serum C-reactive protein, RF: rheumatoid factor (positive ≥15), ACPA: anti-cyclic citrullinated peptide antibody (positive ≥4.5), MMP-3: matrix metalloprotease, DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone, Steinbrocker Stage: Classification of the structural state of rheumatoid arthritis (I, II, III, IV), Steinbrocker Class: Classification of the functional state of rheumatoid arthritis (1, 2, 3, 4), GLM: golimumab Informed consent was obtained in the form of an opt-out on a poster. No patients were excluded. Signed informed consent was not required by the ethics committee because this was a retrospective study. This study was performed according to Declaration of Helsinki and was approved by the Niigata Rheumatic Center ethics committee. The diagnosis of RA was based on the 2010 American College of Rheumatology/EULAR classification criteria (28). Patients who had previously used GLM or had congestive heart failure, active tuberculosis, or active infectious diseases were excluded. The GLM induction and dose were decided by discussion between the treating doctor and the patient based on the EULAR recommendations for the management of RA (17). Although 50 mg of GLM is recommended to be used with MTX in Japan (20), we used 50 mg of GLM without MTX for 2 patients in the naïve group and 6 patients in the switch group. GLM was injected subcutaneously every four weeks at the hospital by the medical staff. We evaluated the age, sex, follow-up period, and history of bDMARDs use, MTX use, and corticosteroid use as patients' baseline characteristics. The RA status was evaluated at 0 and 52 weeks and at the final follow-up based on the following: DAS28-ESR, MTX dose, and PSL dose. The grip power and J-HAQ were also assessed to determine the improvement in the ADL (26). The average grip power of both hands was measured using a mercury dynamometer, which was able to measure from 0 to 300 mmHg (28.9 kg). The patients were divided into bDMARD naïve and switch groups and compared with each other. The continuation rate of GLM was compared between the groups. In addition, we compared the continuation rate of GLM in patients who had and had not been administered MTX. The demographic parameters of patients who did and did not use MTX were also compared. Statistical analyses Statistical analyses were performed using the JMPⓇ 14 software program (SAS Institute, Cary, USA). The chi-square test was used for comparisons between two groups for categorical data, while Wilcoxon's signed rank test was used for continuous variables of paired data. In the comparison of continuous variables (baseline vs. 52 weeks and at final follow-up), 13 patients who discontinued GLM treatment before 52 weeks were excluded. The continuous variables at 52 weeks and at the final follow-up were compared with those at baseline by Wilcoxon's signed rank test adjusted using the Holm method. Regarding the Holm method, first, the p values at 52 weeks and at the final follow-up were compared. If the lower of these p values was <0.025 (0.05/2), the difference was considered significant. If the lower of these p values was ≥0.025, then both p values were considered not significant. If the higher of these p value was <0.05, the difference was considered significant. A one-sided Wilcoxon's signed rank test was performed to evaluate the reduction in the DAS28-ESR, J-HAQ, MTX dose, and PSL dose. In addition, Wilcoxon's signed rank test was performed to evaluate the improvement in the grip power. Spearman correlation analysis was performed to determine the correlation of grip power value, J-HAQ, and DAS28-ESR at the baseline, 52 weeks, and the final follow-up. The Mann-Whitney U test was used to assess continuous variables of non-paired data. To compare the drug continuation rate between both groups, a log-rank test with the Kaplan-Meier method was used. The last observation carried forward (LOCF) method was used for missing data (29). Results Patients' characteristics Sixty-five patients (58 women and 7 men) were included in the present study (Table 1). The median (range) age of patients was 69 (61-74) years old, and the median disease duration was 9 (5-16) years. Among the 65 patients, 28 were biologic-naïve (naïve group), and 37 had switched from biologics (switch group). The median (range) follow-up period was 134 (58-162) weeks. MTX was administered in 66% (43/65) of patients at a median (range) dose of 8.0 (0.0-10.0) mg/week. PSL was administered to 65% (42/65) of patients at a median (range) dose of 3.0 (0.0-5.0) mg/day. Other conventional DMARDs (csDMARDs) were used as follows: salazosulfapyridine in 23 cases (naïve/switch=14/9), mizoribine in 19 cases (5/14), bucillamine in 9 cases (3/6), tacrolimus hydrate in 5 cases (1/4), iguratimod in 4 cases (2/2), and actarit in 4 cases (1/3). In the switch group, 31 patients received GLM as the second bDMARD, 5 patients received it as the third bDMARD, and 1 received it as the fifth bDMARD. Moreover, patients in the switch group received infliximab (IFX) (as the first and second bDMARDs: 18, 1 case), etanercept (ETN) (as the first and second bDMARDs: 13, 3 cases), tocilizumab (TCZ) (as the first and third bDMARD: 4, 1 case), abatacept (ABT) (as the first and fourth bDMARD: 1, 1 case), and adalimumab (ADA) (as first and second bDMARD: 1, 2 cases). There was no significant difference in the baseline status between the naïve and switch groups except for with regard to the rheumatoid factor, MTX dose, Steinbrocker Class, and initial dose of GLM (Table 1) (30). Twenty-four patients in the naïve group received 50 mg GLM; the dose was increased to 100 mg in 13 patients. Fourteen patients in the switch group received 50 mg GLM; the dose was increased to 100 mg in 7 patients. The proportion of patients who were administered 100 mg GLM as the initial dose was higher in the switch group (23/37; 62%) than in the naïve group (4/28; 14%; p<0.001). Efficacy results The median (range) DAS28-ESR value was 4.31 (3.52-5.25) in the naïve group and 4.27 (3.19-4.89) in the switch group at baseline (Table 2). At the final follow-up, the median (range) DAS28-ESR value had improved to 2.65 (2.28-3.77) in the naïve group and 2.89 (2.49-3.88) in the switch group. The J-HAQ did not improve in either group. The ratio of low disease activity and remission improved from naïve 18% (5/28)/switch 24% (9/37) at baseline to naïve 60% (15/25)/switch 52% (14/27) at 52 weeks (p<0.05) and naïve 64% (16/25)/switch 67% (18/27) at the final follow-up (p<0.01) (Fig. 1). The median grip power at 52 weeks and at the final follow-up improved in both groups. The MTX and PSL doses were decreased at the final follow-up. The Spearman correlation coefficients of the grip power, J-HAQ, and DAS28-ESR were ρ=-0.426 (grip power vs. J-HAQ), ρ=-0.417 (grip power vs. DAS28-ESR), and ρ=0.348 (J-HAQ vs. DAS28-ESR) (p<0.001). Table 2. The Clinical Course of Golimumab. Week 0 Week 52 Final follow-up Median (range) Median (range) p value Median (range) p value DAS28-ESR Naïve 4.31 (3.52-5.25) 2.76 (2.23-4.05) <0.001 2.65 (2.28-3.77) <0.001* Switch 4.27 (3.19-4.89) 2.69 (2.19-3.78) 0.001* 2.89 (2.49-3.88) 0.006* Total 4.27 (3.35-4.27) 2.73 (2.22-3.90) <0.001* 2.73 (2.35-3.77) <0.001* J-HAQ Naïve 0.25 (0.04-0.71) 0.25 (0.05-1.03) 0.593 0.23 (0.04-0.80) 0.771 Switch 0.48 (0.25-0.85) 0.53 (0.23-0.88) 0.490 0.53 (0.10-0.85) 0.608 Total 0.40 (0.05-0.84) 0.40 (0.07-0.93) 0.552 0.30 (0.10-0.84) 0.761 Grip power, mmHg Naïve 138 (104-183) 160 (102-231) <0.001* 183 (100-234) 0.041* Switch 127 (93-168) 158 (112-195) 0.026* 154 (115-190) <0.001* Total 133 (96-179) 158 (107-204) <0.001* 165(105-208) <0.001* Dose of MTX, mg/week Naïve 8.0 (6.0-10.0) 8.0 (3.0-8.5) 0.006* 5.0 (0.0-8.0) <0.001* Switch 5.0 (0.0-8.5) 6.0 (0.0-9.0) 0.091 6.0 (0.0-8.0) 0.007* Total 8.0 (0.0-10.0) 7.0 (1.3-8.8) 0.003* 5.5 (0.0-8.0) <0.001* Dose of PSL, mg/day Naïve 2.3 (0.0-5.0) 2.0 (0.0-5.0) 0.110 2.0 (0.0-3.8) 0.016* Switch 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.040 2.5 (0.0-4.0) 0.004* Total 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.016* 2.3 (0.0-4.0) <0.001* At 52 weeks and at the final follow-up, each parameter was compared with the baseline value using the Wilcoxon rank sum test adjusted by the Holm method. *: significant difference. Median (range). DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone Figure 1. The DAS28-ESR at baseline, 52 weeks, and the final follow-up. The DAS28-ESR classification improved from baseline to 52 weeks and at the final follow-up in both groups (chi-square test: p<0.05). The classification of DAS28-ESR was as follows: remission, DAS28-ESR<2.6; low disease activity, 2.6≤DAS28-ESR<3.2; moderate disease activity, 3.2≤DAS28-ESR≤5.1; high disease activity, DAS28-ESR>5.1. DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate Continuation rate and reason for discontinuation The continuation rate at the final follow-up [median (range): 134 (58-162) weeks] was 22/28 (78.6%) in the naïve group and 26/37 (70.3%) in the switch group. The respective continuation rates of the naïve/switch/total groups calculated using the Kaplan-Meier method were 89.3%/73.0%/80.0% at 52 weeks, 81.1%/73.0%/76.4% at 104 weeks, and 76.3%/68.7%/71.6% at 156 weeks (Fig. 2). No significant difference was detected in the continuation rate between the naïve and switch groups (p=0.829). The continuation rate in patients who were administered MTX was higher than that in patients who were not administered MTX (p=0.001; Fig. 3). On comparing the backgrounds of the naïve and switch groups, patients without MTX had higher median (range) values for the age, C-reactive protein (CRP), ESR, matrix metalloprotease-3 (MMP-3), and rheumatoid factor (RF) at baseline than those with MTX (p<0.05) [patients without MTX vs. patients with MTX, age 73 (69-78) vs. 65 (54-70), CRP 1.65 (0.25-3.23) vs. 0.40 (0.10-1.50), ESR 45 (23-80) vs. 18 (10-28), MMP-3 171 (87-367) vs. 95 (60-194), RF 83 (33-162) vs. 23 (13-106)]. Seventeen patients discontinued the administration of GLM. The reasons for discontinuation were as follows: lack of efficacy (8/65: 12.3%), infection (3/65: 4.6%), and eczema, multiple sclerosis, economic reasons, patient preference for bDMARDs, fracture, and transfer to another hospital in 1 case each (1/65: 1.5%). Ten patients (1 naïve, 9 switch) discontinued GLM within 26 weeks, and 3 discontinued GLM between 26 and 52 weeks. Five patients discontinued GLM within 26 weeks because of a lack of efficacy. No patients discontinued GLM due to remission. Figure 2. Drug continuation rates in the naïve and switch groups. The drug continuation rate showed no significant difference between both groups (log rank: p=0.829). Figure 3. Drug continuation rates in groups administered GLM with and without MTX. The group administered GLM with MTX showed a better drug continuation rate than the group administered GLM without MTX (log rank: p=0.004). GLM: golimumab, MTX: methotrexate Discussion In this study, evaluated the effectiveness and continuation rate of GLM for long-term use in daily practice for patients with RA. We recorded the clinical effect and the continuation rate of GLM in daily practice after 52 weeks. As hypothesized, GLM showed effectiveness not only in bDMARD-naïve patients but also in switch patients. In our institution, 38 patients started GLM 50 mg; however, 20 increased the dose to 100 mg because the 50-mg regimen was inadequate. Increasing the dose improved the DAS; therefore, if the 50-mg regimen is not effective, increasing the dose should be considered. The GO-AFTER study has also reported the clinical efficacy of switching to GLM therapy (14). In agreement with this finding, we found that GLM therapy was effective even for the switch group patients. The remission rate of the naïve/switch group was 40% (10/25)/41% (11/27) at 52 weeks and 44% (11/25)/33% (9/27) at the final follow-up. In the GO-FORTH and GO-FORWARD trials, the rates of remission based on the DAS28-ESR were 32.4-52.2% at 52 weeks, 39.4-75.8% at 104 weeks, and 55.3-61.8% at 156 weeks (2,5). In 2 previous studies, the average age at the baseline was 50 years old, and the average DAS28-ESR at the baseline was 5.5-5.9; these patients showed better remission rates at 52 and 104 weeks than did our patients (2,5). In our trial, the median age of the recruited patients was 69 years old. Thus, the age and age-related complications might have affected the remission rate in our patients. In the GO-AFTER trial, the remission rate of the bDMARD switch group for 52/100/160 weeks was 12.5-15.6% for the 50 mg regimen and 21.5-22.1% for the 100 mg regimen (3). The switch group in our study showed a better remission rate than that in the GO-AFTER study. The higher the remission rate of the switch group in our study may have been due to the better DAS28-ESR at baseline than in the GO-AFTER study. In the present study, we recruited older patients than those described in previous studies (16,31,32), and we therefore believe that the 65 patients that were collected from a single institution with 134 (58-162) weeks of follow-up thus provided valuable information in comparison to previous studies. The J-HAQ was not improved at the final follow-up compared with that at the baseline in the present study, which was inconsistent with our hypothesis. The HAQ score in healthy populations was reported to be 0.49 (33). The GO-FORWARD, GO-FORTH, GO-AFTER, and GO-MONO trials reported improvements in the HAQ-DI (0.37-0.75), and the HAQ-DI baseline values ranged from 0.9 to 1.6 (6,31,32,34). In these 4 clinical trials, the mean age ranged from 50-55 years old, and the mean DAS28-ESR ranged from 5.5-6.3. The age and DAS28-ESR were higher in our study than in those previous trials. Furthermore, in our study, 17/65 (26%) patients were classified as Steinbrocker stage III and 34/65 (52%) as Steinbrocker stage IV. Despite the low J-HAQ score (0.40) of our case series at the baseline, the number of patients in the different Steinbrocker classes were as follows: 1 in class 1, 35 in class 2, 27 in class 3, and 2 in class 4. The Steinbrocker Stage and Class in our study indicated that most patients had some irreversible ADL impairments. Furthermore, in the present study, the grip power was correlated with the J-HAQ score (ρ=-0.426, p<0.01) and DAS28-ESR (ρ=-0.417, p<0.01). Therefore, we consider it necessary to evaluate the grip power when assessing subclinical joint dysfunction. Consistent with our hypothesis, in the present study, treatment with GLM improved the grip power at 52 weeks and at the final follow-up. The use of GLM not only suppressed joint inflammation but also improved the grip power. Uutela et al. (35) reported that the grip power reflected the disease status, such as remission, low/moderate disease activity, and high disease activity. The present study showed that the grip power was correlated with the J-HAQ and DAS28-ESR as continuous variables. Eberhardt et al. reported that the use of TNF inhibitors for more than one year in patients with RA improved the grip power. However, details concerning the TNF inhibitors were not provided. As their study findings were published in 2007, GLM would not have been used (27). Aside from the abovementioned study by Eberhardt et al., there have been no reports showing improvements in the grip power following the use of TNF inhibitors. Our study is thus the first to show an improvement in the grip power in daily practice following GLM use. Improving the grip power may promote the prevention of sarcopenia and frailty in the future. Therefore, measuring the grip strength will likely provide supplemental information about potential ADL impairment. Only 17 patients (26.1%) discontinued the treatment course in our study, indicating a high continuation rate for long-term GLM use. The ANSWER cohort study, comprising 2,494 patients in real clinical practice, reported the retention rates of the following 7 bDMARDs: ABT (75.5%), TCZ (71.5%), GLM (65.6%), ETN (61.2%), certolizumab pegol (60.7%), ADA (58.2%), and IFX (53.4%) at 36 months in adjusted model (36). A systematic review by Svedbom et al. reported that the continuation rate of GLM was higher than that of other TNF inhibitors (9). An important characteristic of GLM is its lower antigenicity than other bDMARDs (37). The low antibody production against GLM is likely associated with its high continuity. Svedbom et al. showed that the respective continuation rates of GLM in real clinical practice at 52/104/156 weeks were 67-76%/49-63%/60% for bDMARD-naïve patients and 47-63%/40-61%/32-54% for bDMARD-switch patients (9). Kondo et al. reported that the continuation rate of GLM after 6 years was 50.3% (38). Compared with these data from real clinical practice, our study findings showed a better continuation rate of GLM in both the naïve and switch groups. However, the systematic review by Svedbom et al. included abstracts from academic conferences, which may have provided inadequate information. Therefore, it would be difficult to precisely analyze the reason for the difference between our findings and those of the systematic review. In our study, patients discontinued the treatment course due to a lack of efficacy (8/65: 12.3%), toxic effects (5/65: 7.7%), and other reasons (4/65: 6.2%). None of the patients discontinued the treatment due to remission. In the ANSWER cohort study, the drug retention rate of GLM in the adjusted model at 36 months was as follows: lack of effectiveness (74.0%), toxic effect (89.1%), and remission (92.5%) (28). Ten patients discontinued GLM within 26 weeks, and 3 discontinued between 26 and 52 weeks. Five patients discontinued GLM because of a lack of efficacy within 26 weeks. Kondo et al. reported that the discontinuation of the treatment course frequently occurred within six months (38). A steady-state plasma concentration can be achieved with 12 weeks of repeated injection of GLM (39), which is longer than that of other TNF-inhibitors (40). The GO-FORTH trial results showed that concurrent use of MTX leads to earlier disease control at three and six months than GLM monotherapy and switching therapy [based on the American College of Rheumatology criteria (41)] for two to five years (2,14,16). Considering the discontinuation of drug administration within 26 weeks in the present study, we suggest that tight control of the RA status within 26 weeks is necessary until GLM exhibits effectiveness, especially in monotherapy and switching therapy groups. The continuation rate was higher in patients who were administered MTX than in those who were not. Concurrent use of MTX with GLM decreases immunogenicity and adverse events (42). The patients without MTX were older and had higher CRP, ESR, MMP-3, and RF values than the patients with MTX; therefore, older patients and those with more severe inflammation are likely to be more adversely affected by continuation of GLM. According to the EULAR recommendation (17), if MTX is not contraindicated, it should be administered. It was challenging to administer MTX to patients without MTX because of other medical complications. Our data also showed a reduction in PSL use at the final follow-up, suggesting that the use of PSL for the short term soon after GLM induction would facilitate a decrease in disease activity until GLM exhibits effectiveness up to 26 weeks. Introduction of the 100-mg GLM regimen would facilitate the early suppression of disease and prevent early drop-out from treatment. Several limitations associated with the present study warrant mention. This was a retrospective study, and the sample size was smaller than that of clinical trials. Furthermore, the concurrent use of csDMARDs (including MTX and other csDMARDs) differed among the naïve and switch groups. The final selection and dosage of bDMARDs was decided by discussion between the patient and the doctor. The initial dose of GLM was decided while considering not only the patient's disease status but also their economic status. Our study lacks adequate data to explore the risk of discontinuation using a multivariate analysis, as 17 patients discontinued the study. Conclusion GLM improved the disease activity and grip power in bDMARD-naïve and switch groups. The concurrent use of MTX with GLM showed a better continuation rate than GLM administration without MTX. This is the first report to show the improvement in the grip power by GLM and to demonstrate that the use of GLM can prevent sarcopenia in the future. We also found that the grip power was correlated with the J-HAQ and DAS28-ESR. Our findings concerning the effects of GLM may facilitate further studies on effective RA treatment regimens. Author's disclosure of potential Conflicts of Interest (COI). Satoshi Ito: Honoraria, Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Jansen Pharma and Mitsubishi Tanabe. Hajime Ishikawa: Honoraria, Astellas, Chugai, Gilead Sciences and Corrona.	ABATACEPT, ACTARIT, ADALIMUMAB, BUCILLAMINE, ETANERCEPT, GOLIMUMAB, IGURATIMOD, INFLIXIMAB, METHOTREXATE, MIZORIBINE, PREDNISOLONE, SULFASALAZINE, TACROLIMUS, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC-ND	33250460	18,599,924	2021-05-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eczema'.	Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis. Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA. Introduction The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), such as golimumab (GLM), has transformed the treatment of rheumatoid arthritis (RA). GLM is a human monoclonal IgG antibody that binds to tumor necrosis factor-alpha (TNF-α) (1). GLM in combination with methotrexate (MTX) has shown efficacy and safety in phase III clinical trials (2-4). In Japan, the GO-FORTH (5) and GO-MONO (6) trials demonstrated the clinical efficacy and safety of GLM in combination with MTX and as monotherapy, respectively. Based on these data, the Japanese Pharmaceuticals and Medical Devices Agency approved GLM (50 and 100 mg) as the fourth anti-TNF-α antibody in 2011 (7); the 100 mg dose is only available in Japan (8). Sevedbom et al. performed a systematic review to determine the continuation rate of GLM (9). They identified 12 real-world studies; however, only 3 were original articles, whereas the remaining 9 were abstracts from academic conferences (10-12). There have been a few reports of the 100 mg GLM regimen in daily practice administered once every 4 weeks (8,11,13); these reports had follow-up periods of up to 52 weeks. Shono (13) compared the clinical safety and efficacy between a bio-naïve and bio-switch group and reported that the improvement in disease activity was similar between the groups at 24 weeks. Although the GO-FORWARD, GO-AFTER, GO-BEFORE, and GO-MONO studies were randomized controlled trials to show the efficacy and safety of GLM from 120 weeks to 5 years, they differed from studies in real clinical settings (2,14-16). The European League Against Rheumatism (EULAR) has recommended the short-term use of prednisolone (PSL) to control disease activity (17). Since a high dose of PSL has many adverse effects, reducing the dose is useful (18). MTX plays an important role in the treatment of RA, but it also has side effects (19), causing many patients to wish to taper or discontinue MTX therapy (20). Since the introduction of the treat-to-target strategy, patients have sought to achieve a high quality of life (QOL). The Japanese version of the health assessment questionnaire (J-HAQ) is an instrument for measuring the physical function and health-related QOL (21). Sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance” by the Asian Working Group for Sarcopenia in 2014, with a consensus update in 2019 (22). The diagnostic criterion of “low muscle strength” is defined as a grip power <28 kg for men and <18 kg for women. Sarcopenia enhances the fall burden, decreases healthy life expectancy, and increases healthcare costs (23,24). Previous reports on the prevalence of sarcopenia have varied; for example, a meta-analysis showed that the prevalence of sarcopenia in patients with RA was 15-32% (25), and Torii et al. reported a prevalence of 37.1% in Japanese patients (23). In addition, Ishikawa et al. reported that the handgrip power in Japanese patients with RA reflects the level of independence in activity of daily living (ADL), and the cut-off value for independent ADL was 136.5 mmHg (11.8 kgw) for women and 152.5 mmHg (13.5 kgw) for men (26). Only one report has described an improvement in the grip power following the use of bDMARDs, with the use of TNF inhibitors for more than one year being shown to improve the grip power in patients with RA (27). We hypothesized that improving the grip power can not only ameliorate inflammation in the upper extremities in patients with RA but also decrease sarcopenia and increase the healthy life expectancy. We hypothesized that the long-term use of GLM would be safe and effective in bio-naïve and bio-switch patients in real clinical practice and that the use of GLM would facilitate better disease control, reduce the PSL and MTX dosages, and improve the J-HAQ and grip power. Furthermore, we hypothesized that the grip power correlates with the J-HAQ score and Disease Activity Score (DAS) 28-ESR. Therefore, in the present study, we evaluated the effectiveness and drug continuation rate of long-term use of GLM in bDMARD-naïve and switch patients in clinical practice in order to determine the reason for discontinuation because of a lack of efficacy. Materials and Methods We retrospectively analyzed the data of patients with RA administered GLM at Niigata Rheumatic Center from October 2011 to March 2015. Sixty-five patients (58 women and 7 men) started GLM therapy during this period. All patients were followed up for more than 52 weeks. Data were collected in March 2016 and retrospectively analyzed (Table 1). The patients were divided into bDMARD “naïve” and “switch” groups based on their history of use. Table 1. Characteristics of Patients in the Naïve and Switch Groups. Total (n=65) Naïve (n=28) Switch (n=37) p value Female, n (%) 58 (89%) 25 (89%) 33 (89%) 0.990 Age, years 69 (61-74) 68 (60-71) 70 (60-76) 0.180 Disease duration of RA, years 9 (5-16) 10 (2-20) 9 (7-16) 0.418 Follow up period 134 (58-162) 127 (79-148) 142 (80-170) 0.310 Swollen joint count 3 (1-6) 3 (1-6) 2 (0-6) 0.414 Tender joint count 3 (1-6) 4 (1-8) 2 (1-5) 0.149 Patient’s global VAS score, mm 46 (23-59) 47 (25-60) 46 (21-59) 0.842 Doctor’s global VAS score, mm 35 (23-60) 40 (26-60) 35 (19-52) 0.524 ESR, mm/h 23 (12-50) 24 (10-49) 23 (14-50) 0.628 CRP, mg/dL 0.60 (0.10-2.10) 0.40 (0.1-1.8) 0.80 (0.10-2.55) 0.110 RF, IU/mL 47 (18-112) 73 (21-231) 43 (11-99) 0.040* RF, positive (%) 49 (75%) 26 (93%) 23 (62%) 0.003* ACPA, U/mL 88 (22-244) 117 (22-248) 67 (25-213) 0.367 ACPA, positive (%) 57 (87%) 26 (93%) 31 (84%) 0.172 MMP-3, ng/mL 128 (67-214) 93 (62-171) 142 (70-249) 0.161 DAS28-ESR 4.27 (3.35-5.19) 4.31 (3.52-5.25) 4.27 (3.19-4.89) 0.521 J-HAQ 0.40 (0.05-0.84) 0.25 (0.04-0.71) 0.48(0.21-0.88) 0.223 MTX use, n (%) 43 (66%) 22 (79%) 21 (57%) 0.066 Dose of MTX, mg/week 8.0 (0.0-10.0) 8.0 (6.0-10.0) 5.0 (0.0-8.5) 0.046* PSL use, n (%) 42(65%) 16 (57%) 26 (70%) 0.299 Dose of PSL, mg/day 3.0 (0.0-5.0) 2.3 (0.0-5.0) 3.0 (0.0-5.0) 0.299 Steinbrocker Stage (I, II, III, IV) 4:10:17:34 3:5:6:14 1:5:11:20 0.507 Steinbrocker Class (1, 2, 3, 4) 1:35:27:2 1:20:7:0 0:15:20:2 0.030* Initial dose of GLM (50 mg:100 mg) 38:27 24:4 14:23 <0.001** Number of patients with dose escalation, n (%) 20 (31%) 13 (46%) 7 (19%) 0.017* Number of patients who discontinued treatment, n (%) 17 (26%) 6 (21%) 11 (30%) 0.450 P value was calculated by comparing naïve and switch groups. A chi-square test was used for comparison of categorical data between the two groups. The Mann-Whitney U test was used to assess continuous variables of non-paired data. : p<0.05, : p<0.01. Median (range). RA: rheumatoid arthritis, VAS: visual analog scale, ESR: erythrocyte sedimentation rate, CRP: the serum C-reactive protein, RF: rheumatoid factor (positive ≥15), ACPA: anti-cyclic citrullinated peptide antibody (positive ≥4.5), MMP-3: matrix metalloprotease, DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone, Steinbrocker Stage: Classification of the structural state of rheumatoid arthritis (I, II, III, IV), Steinbrocker Class: Classification of the functional state of rheumatoid arthritis (1, 2, 3, 4), GLM: golimumab Informed consent was obtained in the form of an opt-out on a poster. No patients were excluded. Signed informed consent was not required by the ethics committee because this was a retrospective study. This study was performed according to Declaration of Helsinki and was approved by the Niigata Rheumatic Center ethics committee. The diagnosis of RA was based on the 2010 American College of Rheumatology/EULAR classification criteria (28). Patients who had previously used GLM or had congestive heart failure, active tuberculosis, or active infectious diseases were excluded. The GLM induction and dose were decided by discussion between the treating doctor and the patient based on the EULAR recommendations for the management of RA (17). Although 50 mg of GLM is recommended to be used with MTX in Japan (20), we used 50 mg of GLM without MTX for 2 patients in the naïve group and 6 patients in the switch group. GLM was injected subcutaneously every four weeks at the hospital by the medical staff. We evaluated the age, sex, follow-up period, and history of bDMARDs use, MTX use, and corticosteroid use as patients' baseline characteristics. The RA status was evaluated at 0 and 52 weeks and at the final follow-up based on the following: DAS28-ESR, MTX dose, and PSL dose. The grip power and J-HAQ were also assessed to determine the improvement in the ADL (26). The average grip power of both hands was measured using a mercury dynamometer, which was able to measure from 0 to 300 mmHg (28.9 kg). The patients were divided into bDMARD naïve and switch groups and compared with each other. The continuation rate of GLM was compared between the groups. In addition, we compared the continuation rate of GLM in patients who had and had not been administered MTX. The demographic parameters of patients who did and did not use MTX were also compared. Statistical analyses Statistical analyses were performed using the JMPⓇ 14 software program (SAS Institute, Cary, USA). The chi-square test was used for comparisons between two groups for categorical data, while Wilcoxon's signed rank test was used for continuous variables of paired data. In the comparison of continuous variables (baseline vs. 52 weeks and at final follow-up), 13 patients who discontinued GLM treatment before 52 weeks were excluded. The continuous variables at 52 weeks and at the final follow-up were compared with those at baseline by Wilcoxon's signed rank test adjusted using the Holm method. Regarding the Holm method, first, the p values at 52 weeks and at the final follow-up were compared. If the lower of these p values was <0.025 (0.05/2), the difference was considered significant. If the lower of these p values was ≥0.025, then both p values were considered not significant. If the higher of these p value was <0.05, the difference was considered significant. A one-sided Wilcoxon's signed rank test was performed to evaluate the reduction in the DAS28-ESR, J-HAQ, MTX dose, and PSL dose. In addition, Wilcoxon's signed rank test was performed to evaluate the improvement in the grip power. Spearman correlation analysis was performed to determine the correlation of grip power value, J-HAQ, and DAS28-ESR at the baseline, 52 weeks, and the final follow-up. The Mann-Whitney U test was used to assess continuous variables of non-paired data. To compare the drug continuation rate between both groups, a log-rank test with the Kaplan-Meier method was used. The last observation carried forward (LOCF) method was used for missing data (29). Results Patients' characteristics Sixty-five patients (58 women and 7 men) were included in the present study (Table 1). The median (range) age of patients was 69 (61-74) years old, and the median disease duration was 9 (5-16) years. Among the 65 patients, 28 were biologic-naïve (naïve group), and 37 had switched from biologics (switch group). The median (range) follow-up period was 134 (58-162) weeks. MTX was administered in 66% (43/65) of patients at a median (range) dose of 8.0 (0.0-10.0) mg/week. PSL was administered to 65% (42/65) of patients at a median (range) dose of 3.0 (0.0-5.0) mg/day. Other conventional DMARDs (csDMARDs) were used as follows: salazosulfapyridine in 23 cases (naïve/switch=14/9), mizoribine in 19 cases (5/14), bucillamine in 9 cases (3/6), tacrolimus hydrate in 5 cases (1/4), iguratimod in 4 cases (2/2), and actarit in 4 cases (1/3). In the switch group, 31 patients received GLM as the second bDMARD, 5 patients received it as the third bDMARD, and 1 received it as the fifth bDMARD. Moreover, patients in the switch group received infliximab (IFX) (as the first and second bDMARDs: 18, 1 case), etanercept (ETN) (as the first and second bDMARDs: 13, 3 cases), tocilizumab (TCZ) (as the first and third bDMARD: 4, 1 case), abatacept (ABT) (as the first and fourth bDMARD: 1, 1 case), and adalimumab (ADA) (as first and second bDMARD: 1, 2 cases). There was no significant difference in the baseline status between the naïve and switch groups except for with regard to the rheumatoid factor, MTX dose, Steinbrocker Class, and initial dose of GLM (Table 1) (30). Twenty-four patients in the naïve group received 50 mg GLM; the dose was increased to 100 mg in 13 patients. Fourteen patients in the switch group received 50 mg GLM; the dose was increased to 100 mg in 7 patients. The proportion of patients who were administered 100 mg GLM as the initial dose was higher in the switch group (23/37; 62%) than in the naïve group (4/28; 14%; p<0.001). Efficacy results The median (range) DAS28-ESR value was 4.31 (3.52-5.25) in the naïve group and 4.27 (3.19-4.89) in the switch group at baseline (Table 2). At the final follow-up, the median (range) DAS28-ESR value had improved to 2.65 (2.28-3.77) in the naïve group and 2.89 (2.49-3.88) in the switch group. The J-HAQ did not improve in either group. The ratio of low disease activity and remission improved from naïve 18% (5/28)/switch 24% (9/37) at baseline to naïve 60% (15/25)/switch 52% (14/27) at 52 weeks (p<0.05) and naïve 64% (16/25)/switch 67% (18/27) at the final follow-up (p<0.01) (Fig. 1). The median grip power at 52 weeks and at the final follow-up improved in both groups. The MTX and PSL doses were decreased at the final follow-up. The Spearman correlation coefficients of the grip power, J-HAQ, and DAS28-ESR were ρ=-0.426 (grip power vs. J-HAQ), ρ=-0.417 (grip power vs. DAS28-ESR), and ρ=0.348 (J-HAQ vs. DAS28-ESR) (p<0.001). Table 2. The Clinical Course of Golimumab. Week 0 Week 52 Final follow-up Median (range) Median (range) p value Median (range) p value DAS28-ESR Naïve 4.31 (3.52-5.25) 2.76 (2.23-4.05) <0.001 2.65 (2.28-3.77) <0.001* Switch 4.27 (3.19-4.89) 2.69 (2.19-3.78) 0.001* 2.89 (2.49-3.88) 0.006* Total 4.27 (3.35-4.27) 2.73 (2.22-3.90) <0.001* 2.73 (2.35-3.77) <0.001* J-HAQ Naïve 0.25 (0.04-0.71) 0.25 (0.05-1.03) 0.593 0.23 (0.04-0.80) 0.771 Switch 0.48 (0.25-0.85) 0.53 (0.23-0.88) 0.490 0.53 (0.10-0.85) 0.608 Total 0.40 (0.05-0.84) 0.40 (0.07-0.93) 0.552 0.30 (0.10-0.84) 0.761 Grip power, mmHg Naïve 138 (104-183) 160 (102-231) <0.001* 183 (100-234) 0.041* Switch 127 (93-168) 158 (112-195) 0.026* 154 (115-190) <0.001* Total 133 (96-179) 158 (107-204) <0.001* 165(105-208) <0.001* Dose of MTX, mg/week Naïve 8.0 (6.0-10.0) 8.0 (3.0-8.5) 0.006* 5.0 (0.0-8.0) <0.001* Switch 5.0 (0.0-8.5) 6.0 (0.0-9.0) 0.091 6.0 (0.0-8.0) 0.007* Total 8.0 (0.0-10.0) 7.0 (1.3-8.8) 0.003* 5.5 (0.0-8.0) <0.001* Dose of PSL, mg/day Naïve 2.3 (0.0-5.0) 2.0 (0.0-5.0) 0.110 2.0 (0.0-3.8) 0.016* Switch 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.040 2.5 (0.0-4.0) 0.004* Total 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.016* 2.3 (0.0-4.0) <0.001* At 52 weeks and at the final follow-up, each parameter was compared with the baseline value using the Wilcoxon rank sum test adjusted by the Holm method. *: significant difference. Median (range). DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone Figure 1. The DAS28-ESR at baseline, 52 weeks, and the final follow-up. The DAS28-ESR classification improved from baseline to 52 weeks and at the final follow-up in both groups (chi-square test: p<0.05). The classification of DAS28-ESR was as follows: remission, DAS28-ESR<2.6; low disease activity, 2.6≤DAS28-ESR<3.2; moderate disease activity, 3.2≤DAS28-ESR≤5.1; high disease activity, DAS28-ESR>5.1. DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate Continuation rate and reason for discontinuation The continuation rate at the final follow-up [median (range): 134 (58-162) weeks] was 22/28 (78.6%) in the naïve group and 26/37 (70.3%) in the switch group. The respective continuation rates of the naïve/switch/total groups calculated using the Kaplan-Meier method were 89.3%/73.0%/80.0% at 52 weeks, 81.1%/73.0%/76.4% at 104 weeks, and 76.3%/68.7%/71.6% at 156 weeks (Fig. 2). No significant difference was detected in the continuation rate between the naïve and switch groups (p=0.829). The continuation rate in patients who were administered MTX was higher than that in patients who were not administered MTX (p=0.001; Fig. 3). On comparing the backgrounds of the naïve and switch groups, patients without MTX had higher median (range) values for the age, C-reactive protein (CRP), ESR, matrix metalloprotease-3 (MMP-3), and rheumatoid factor (RF) at baseline than those with MTX (p<0.05) [patients without MTX vs. patients with MTX, age 73 (69-78) vs. 65 (54-70), CRP 1.65 (0.25-3.23) vs. 0.40 (0.10-1.50), ESR 45 (23-80) vs. 18 (10-28), MMP-3 171 (87-367) vs. 95 (60-194), RF 83 (33-162) vs. 23 (13-106)]. Seventeen patients discontinued the administration of GLM. The reasons for discontinuation were as follows: lack of efficacy (8/65: 12.3%), infection (3/65: 4.6%), and eczema, multiple sclerosis, economic reasons, patient preference for bDMARDs, fracture, and transfer to another hospital in 1 case each (1/65: 1.5%). Ten patients (1 naïve, 9 switch) discontinued GLM within 26 weeks, and 3 discontinued GLM between 26 and 52 weeks. Five patients discontinued GLM within 26 weeks because of a lack of efficacy. No patients discontinued GLM due to remission. Figure 2. Drug continuation rates in the naïve and switch groups. The drug continuation rate showed no significant difference between both groups (log rank: p=0.829). Figure 3. Drug continuation rates in groups administered GLM with and without MTX. The group administered GLM with MTX showed a better drug continuation rate than the group administered GLM without MTX (log rank: p=0.004). GLM: golimumab, MTX: methotrexate Discussion In this study, evaluated the effectiveness and continuation rate of GLM for long-term use in daily practice for patients with RA. We recorded the clinical effect and the continuation rate of GLM in daily practice after 52 weeks. As hypothesized, GLM showed effectiveness not only in bDMARD-naïve patients but also in switch patients. In our institution, 38 patients started GLM 50 mg; however, 20 increased the dose to 100 mg because the 50-mg regimen was inadequate. Increasing the dose improved the DAS; therefore, if the 50-mg regimen is not effective, increasing the dose should be considered. The GO-AFTER study has also reported the clinical efficacy of switching to GLM therapy (14). In agreement with this finding, we found that GLM therapy was effective even for the switch group patients. The remission rate of the naïve/switch group was 40% (10/25)/41% (11/27) at 52 weeks and 44% (11/25)/33% (9/27) at the final follow-up. In the GO-FORTH and GO-FORWARD trials, the rates of remission based on the DAS28-ESR were 32.4-52.2% at 52 weeks, 39.4-75.8% at 104 weeks, and 55.3-61.8% at 156 weeks (2,5). In 2 previous studies, the average age at the baseline was 50 years old, and the average DAS28-ESR at the baseline was 5.5-5.9; these patients showed better remission rates at 52 and 104 weeks than did our patients (2,5). In our trial, the median age of the recruited patients was 69 years old. Thus, the age and age-related complications might have affected the remission rate in our patients. In the GO-AFTER trial, the remission rate of the bDMARD switch group for 52/100/160 weeks was 12.5-15.6% for the 50 mg regimen and 21.5-22.1% for the 100 mg regimen (3). The switch group in our study showed a better remission rate than that in the GO-AFTER study. The higher the remission rate of the switch group in our study may have been due to the better DAS28-ESR at baseline than in the GO-AFTER study. In the present study, we recruited older patients than those described in previous studies (16,31,32), and we therefore believe that the 65 patients that were collected from a single institution with 134 (58-162) weeks of follow-up thus provided valuable information in comparison to previous studies. The J-HAQ was not improved at the final follow-up compared with that at the baseline in the present study, which was inconsistent with our hypothesis. The HAQ score in healthy populations was reported to be 0.49 (33). The GO-FORWARD, GO-FORTH, GO-AFTER, and GO-MONO trials reported improvements in the HAQ-DI (0.37-0.75), and the HAQ-DI baseline values ranged from 0.9 to 1.6 (6,31,32,34). In these 4 clinical trials, the mean age ranged from 50-55 years old, and the mean DAS28-ESR ranged from 5.5-6.3. The age and DAS28-ESR were higher in our study than in those previous trials. Furthermore, in our study, 17/65 (26%) patients were classified as Steinbrocker stage III and 34/65 (52%) as Steinbrocker stage IV. Despite the low J-HAQ score (0.40) of our case series at the baseline, the number of patients in the different Steinbrocker classes were as follows: 1 in class 1, 35 in class 2, 27 in class 3, and 2 in class 4. The Steinbrocker Stage and Class in our study indicated that most patients had some irreversible ADL impairments. Furthermore, in the present study, the grip power was correlated with the J-HAQ score (ρ=-0.426, p<0.01) and DAS28-ESR (ρ=-0.417, p<0.01). Therefore, we consider it necessary to evaluate the grip power when assessing subclinical joint dysfunction. Consistent with our hypothesis, in the present study, treatment with GLM improved the grip power at 52 weeks and at the final follow-up. The use of GLM not only suppressed joint inflammation but also improved the grip power. Uutela et al. (35) reported that the grip power reflected the disease status, such as remission, low/moderate disease activity, and high disease activity. The present study showed that the grip power was correlated with the J-HAQ and DAS28-ESR as continuous variables. Eberhardt et al. reported that the use of TNF inhibitors for more than one year in patients with RA improved the grip power. However, details concerning the TNF inhibitors were not provided. As their study findings were published in 2007, GLM would not have been used (27). Aside from the abovementioned study by Eberhardt et al., there have been no reports showing improvements in the grip power following the use of TNF inhibitors. Our study is thus the first to show an improvement in the grip power in daily practice following GLM use. Improving the grip power may promote the prevention of sarcopenia and frailty in the future. Therefore, measuring the grip strength will likely provide supplemental information about potential ADL impairment. Only 17 patients (26.1%) discontinued the treatment course in our study, indicating a high continuation rate for long-term GLM use. The ANSWER cohort study, comprising 2,494 patients in real clinical practice, reported the retention rates of the following 7 bDMARDs: ABT (75.5%), TCZ (71.5%), GLM (65.6%), ETN (61.2%), certolizumab pegol (60.7%), ADA (58.2%), and IFX (53.4%) at 36 months in adjusted model (36). A systematic review by Svedbom et al. reported that the continuation rate of GLM was higher than that of other TNF inhibitors (9). An important characteristic of GLM is its lower antigenicity than other bDMARDs (37). The low antibody production against GLM is likely associated with its high continuity. Svedbom et al. showed that the respective continuation rates of GLM in real clinical practice at 52/104/156 weeks were 67-76%/49-63%/60% for bDMARD-naïve patients and 47-63%/40-61%/32-54% for bDMARD-switch patients (9). Kondo et al. reported that the continuation rate of GLM after 6 years was 50.3% (38). Compared with these data from real clinical practice, our study findings showed a better continuation rate of GLM in both the naïve and switch groups. However, the systematic review by Svedbom et al. included abstracts from academic conferences, which may have provided inadequate information. Therefore, it would be difficult to precisely analyze the reason for the difference between our findings and those of the systematic review. In our study, patients discontinued the treatment course due to a lack of efficacy (8/65: 12.3%), toxic effects (5/65: 7.7%), and other reasons (4/65: 6.2%). None of the patients discontinued the treatment due to remission. In the ANSWER cohort study, the drug retention rate of GLM in the adjusted model at 36 months was as follows: lack of effectiveness (74.0%), toxic effect (89.1%), and remission (92.5%) (28). Ten patients discontinued GLM within 26 weeks, and 3 discontinued between 26 and 52 weeks. Five patients discontinued GLM because of a lack of efficacy within 26 weeks. Kondo et al. reported that the discontinuation of the treatment course frequently occurred within six months (38). A steady-state plasma concentration can be achieved with 12 weeks of repeated injection of GLM (39), which is longer than that of other TNF-inhibitors (40). The GO-FORTH trial results showed that concurrent use of MTX leads to earlier disease control at three and six months than GLM monotherapy and switching therapy [based on the American College of Rheumatology criteria (41)] for two to five years (2,14,16). Considering the discontinuation of drug administration within 26 weeks in the present study, we suggest that tight control of the RA status within 26 weeks is necessary until GLM exhibits effectiveness, especially in monotherapy and switching therapy groups. The continuation rate was higher in patients who were administered MTX than in those who were not. Concurrent use of MTX with GLM decreases immunogenicity and adverse events (42). The patients without MTX were older and had higher CRP, ESR, MMP-3, and RF values than the patients with MTX; therefore, older patients and those with more severe inflammation are likely to be more adversely affected by continuation of GLM. According to the EULAR recommendation (17), if MTX is not contraindicated, it should be administered. It was challenging to administer MTX to patients without MTX because of other medical complications. Our data also showed a reduction in PSL use at the final follow-up, suggesting that the use of PSL for the short term soon after GLM induction would facilitate a decrease in disease activity until GLM exhibits effectiveness up to 26 weeks. Introduction of the 100-mg GLM regimen would facilitate the early suppression of disease and prevent early drop-out from treatment. Several limitations associated with the present study warrant mention. This was a retrospective study, and the sample size was smaller than that of clinical trials. Furthermore, the concurrent use of csDMARDs (including MTX and other csDMARDs) differed among the naïve and switch groups. The final selection and dosage of bDMARDs was decided by discussion between the patient and the doctor. The initial dose of GLM was decided while considering not only the patient's disease status but also their economic status. Our study lacks adequate data to explore the risk of discontinuation using a multivariate analysis, as 17 patients discontinued the study. Conclusion GLM improved the disease activity and grip power in bDMARD-naïve and switch groups. The concurrent use of MTX with GLM showed a better continuation rate than GLM administration without MTX. This is the first report to show the improvement in the grip power by GLM and to demonstrate that the use of GLM can prevent sarcopenia in the future. We also found that the grip power was correlated with the J-HAQ and DAS28-ESR. Our findings concerning the effects of GLM may facilitate further studies on effective RA treatment regimens. Author's disclosure of potential Conflicts of Interest (COI). Satoshi Ito: Honoraria, Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Jansen Pharma and Mitsubishi Tanabe. Hajime Ishikawa: Honoraria, Astellas, Chugai, Gilead Sciences and Corrona.	ABATACEPT, ACTARIT, ADALIMUMAB, BUCILLAMINE, ETANERCEPT, GOLIMUMAB, IGURATIMOD, INFLIXIMAB, METHOTREXATE, MIZORIBINE, PREDNISOLONE, SULFASALAZINE, TACROLIMUS, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC-ND	33250460	18,599,924	2021-05-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'.	Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis. Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA. Introduction The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), such as golimumab (GLM), has transformed the treatment of rheumatoid arthritis (RA). GLM is a human monoclonal IgG antibody that binds to tumor necrosis factor-alpha (TNF-α) (1). GLM in combination with methotrexate (MTX) has shown efficacy and safety in phase III clinical trials (2-4). In Japan, the GO-FORTH (5) and GO-MONO (6) trials demonstrated the clinical efficacy and safety of GLM in combination with MTX and as monotherapy, respectively. Based on these data, the Japanese Pharmaceuticals and Medical Devices Agency approved GLM (50 and 100 mg) as the fourth anti-TNF-α antibody in 2011 (7); the 100 mg dose is only available in Japan (8). Sevedbom et al. performed a systematic review to determine the continuation rate of GLM (9). They identified 12 real-world studies; however, only 3 were original articles, whereas the remaining 9 were abstracts from academic conferences (10-12). There have been a few reports of the 100 mg GLM regimen in daily practice administered once every 4 weeks (8,11,13); these reports had follow-up periods of up to 52 weeks. Shono (13) compared the clinical safety and efficacy between a bio-naïve and bio-switch group and reported that the improvement in disease activity was similar between the groups at 24 weeks. Although the GO-FORWARD, GO-AFTER, GO-BEFORE, and GO-MONO studies were randomized controlled trials to show the efficacy and safety of GLM from 120 weeks to 5 years, they differed from studies in real clinical settings (2,14-16). The European League Against Rheumatism (EULAR) has recommended the short-term use of prednisolone (PSL) to control disease activity (17). Since a high dose of PSL has many adverse effects, reducing the dose is useful (18). MTX plays an important role in the treatment of RA, but it also has side effects (19), causing many patients to wish to taper or discontinue MTX therapy (20). Since the introduction of the treat-to-target strategy, patients have sought to achieve a high quality of life (QOL). The Japanese version of the health assessment questionnaire (J-HAQ) is an instrument for measuring the physical function and health-related QOL (21). Sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance” by the Asian Working Group for Sarcopenia in 2014, with a consensus update in 2019 (22). The diagnostic criterion of “low muscle strength” is defined as a grip power <28 kg for men and <18 kg for women. Sarcopenia enhances the fall burden, decreases healthy life expectancy, and increases healthcare costs (23,24). Previous reports on the prevalence of sarcopenia have varied; for example, a meta-analysis showed that the prevalence of sarcopenia in patients with RA was 15-32% (25), and Torii et al. reported a prevalence of 37.1% in Japanese patients (23). In addition, Ishikawa et al. reported that the handgrip power in Japanese patients with RA reflects the level of independence in activity of daily living (ADL), and the cut-off value for independent ADL was 136.5 mmHg (11.8 kgw) for women and 152.5 mmHg (13.5 kgw) for men (26). Only one report has described an improvement in the grip power following the use of bDMARDs, with the use of TNF inhibitors for more than one year being shown to improve the grip power in patients with RA (27). We hypothesized that improving the grip power can not only ameliorate inflammation in the upper extremities in patients with RA but also decrease sarcopenia and increase the healthy life expectancy. We hypothesized that the long-term use of GLM would be safe and effective in bio-naïve and bio-switch patients in real clinical practice and that the use of GLM would facilitate better disease control, reduce the PSL and MTX dosages, and improve the J-HAQ and grip power. Furthermore, we hypothesized that the grip power correlates with the J-HAQ score and Disease Activity Score (DAS) 28-ESR. Therefore, in the present study, we evaluated the effectiveness and drug continuation rate of long-term use of GLM in bDMARD-naïve and switch patients in clinical practice in order to determine the reason for discontinuation because of a lack of efficacy. Materials and Methods We retrospectively analyzed the data of patients with RA administered GLM at Niigata Rheumatic Center from October 2011 to March 2015. Sixty-five patients (58 women and 7 men) started GLM therapy during this period. All patients were followed up for more than 52 weeks. Data were collected in March 2016 and retrospectively analyzed (Table 1). The patients were divided into bDMARD “naïve” and “switch” groups based on their history of use. Table 1. Characteristics of Patients in the Naïve and Switch Groups. Total (n=65) Naïve (n=28) Switch (n=37) p value Female, n (%) 58 (89%) 25 (89%) 33 (89%) 0.990 Age, years 69 (61-74) 68 (60-71) 70 (60-76) 0.180 Disease duration of RA, years 9 (5-16) 10 (2-20) 9 (7-16) 0.418 Follow up period 134 (58-162) 127 (79-148) 142 (80-170) 0.310 Swollen joint count 3 (1-6) 3 (1-6) 2 (0-6) 0.414 Tender joint count 3 (1-6) 4 (1-8) 2 (1-5) 0.149 Patient’s global VAS score, mm 46 (23-59) 47 (25-60) 46 (21-59) 0.842 Doctor’s global VAS score, mm 35 (23-60) 40 (26-60) 35 (19-52) 0.524 ESR, mm/h 23 (12-50) 24 (10-49) 23 (14-50) 0.628 CRP, mg/dL 0.60 (0.10-2.10) 0.40 (0.1-1.8) 0.80 (0.10-2.55) 0.110 RF, IU/mL 47 (18-112) 73 (21-231) 43 (11-99) 0.040* RF, positive (%) 49 (75%) 26 (93%) 23 (62%) 0.003* ACPA, U/mL 88 (22-244) 117 (22-248) 67 (25-213) 0.367 ACPA, positive (%) 57 (87%) 26 (93%) 31 (84%) 0.172 MMP-3, ng/mL 128 (67-214) 93 (62-171) 142 (70-249) 0.161 DAS28-ESR 4.27 (3.35-5.19) 4.31 (3.52-5.25) 4.27 (3.19-4.89) 0.521 J-HAQ 0.40 (0.05-0.84) 0.25 (0.04-0.71) 0.48(0.21-0.88) 0.223 MTX use, n (%) 43 (66%) 22 (79%) 21 (57%) 0.066 Dose of MTX, mg/week 8.0 (0.0-10.0) 8.0 (6.0-10.0) 5.0 (0.0-8.5) 0.046* PSL use, n (%) 42(65%) 16 (57%) 26 (70%) 0.299 Dose of PSL, mg/day 3.0 (0.0-5.0) 2.3 (0.0-5.0) 3.0 (0.0-5.0) 0.299 Steinbrocker Stage (I, II, III, IV) 4:10:17:34 3:5:6:14 1:5:11:20 0.507 Steinbrocker Class (1, 2, 3, 4) 1:35:27:2 1:20:7:0 0:15:20:2 0.030* Initial dose of GLM (50 mg:100 mg) 38:27 24:4 14:23 <0.001** Number of patients with dose escalation, n (%) 20 (31%) 13 (46%) 7 (19%) 0.017* Number of patients who discontinued treatment, n (%) 17 (26%) 6 (21%) 11 (30%) 0.450 P value was calculated by comparing naïve and switch groups. A chi-square test was used for comparison of categorical data between the two groups. The Mann-Whitney U test was used to assess continuous variables of non-paired data. : p<0.05, : p<0.01. Median (range). RA: rheumatoid arthritis, VAS: visual analog scale, ESR: erythrocyte sedimentation rate, CRP: the serum C-reactive protein, RF: rheumatoid factor (positive ≥15), ACPA: anti-cyclic citrullinated peptide antibody (positive ≥4.5), MMP-3: matrix metalloprotease, DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone, Steinbrocker Stage: Classification of the structural state of rheumatoid arthritis (I, II, III, IV), Steinbrocker Class: Classification of the functional state of rheumatoid arthritis (1, 2, 3, 4), GLM: golimumab Informed consent was obtained in the form of an opt-out on a poster. No patients were excluded. Signed informed consent was not required by the ethics committee because this was a retrospective study. This study was performed according to Declaration of Helsinki and was approved by the Niigata Rheumatic Center ethics committee. The diagnosis of RA was based on the 2010 American College of Rheumatology/EULAR classification criteria (28). Patients who had previously used GLM or had congestive heart failure, active tuberculosis, or active infectious diseases were excluded. The GLM induction and dose were decided by discussion between the treating doctor and the patient based on the EULAR recommendations for the management of RA (17). Although 50 mg of GLM is recommended to be used with MTX in Japan (20), we used 50 mg of GLM without MTX for 2 patients in the naïve group and 6 patients in the switch group. GLM was injected subcutaneously every four weeks at the hospital by the medical staff. We evaluated the age, sex, follow-up period, and history of bDMARDs use, MTX use, and corticosteroid use as patients' baseline characteristics. The RA status was evaluated at 0 and 52 weeks and at the final follow-up based on the following: DAS28-ESR, MTX dose, and PSL dose. The grip power and J-HAQ were also assessed to determine the improvement in the ADL (26). The average grip power of both hands was measured using a mercury dynamometer, which was able to measure from 0 to 300 mmHg (28.9 kg). The patients were divided into bDMARD naïve and switch groups and compared with each other. The continuation rate of GLM was compared between the groups. In addition, we compared the continuation rate of GLM in patients who had and had not been administered MTX. The demographic parameters of patients who did and did not use MTX were also compared. Statistical analyses Statistical analyses were performed using the JMPⓇ 14 software program (SAS Institute, Cary, USA). The chi-square test was used for comparisons between two groups for categorical data, while Wilcoxon's signed rank test was used for continuous variables of paired data. In the comparison of continuous variables (baseline vs. 52 weeks and at final follow-up), 13 patients who discontinued GLM treatment before 52 weeks were excluded. The continuous variables at 52 weeks and at the final follow-up were compared with those at baseline by Wilcoxon's signed rank test adjusted using the Holm method. Regarding the Holm method, first, the p values at 52 weeks and at the final follow-up were compared. If the lower of these p values was <0.025 (0.05/2), the difference was considered significant. If the lower of these p values was ≥0.025, then both p values were considered not significant. If the higher of these p value was <0.05, the difference was considered significant. A one-sided Wilcoxon's signed rank test was performed to evaluate the reduction in the DAS28-ESR, J-HAQ, MTX dose, and PSL dose. In addition, Wilcoxon's signed rank test was performed to evaluate the improvement in the grip power. Spearman correlation analysis was performed to determine the correlation of grip power value, J-HAQ, and DAS28-ESR at the baseline, 52 weeks, and the final follow-up. The Mann-Whitney U test was used to assess continuous variables of non-paired data. To compare the drug continuation rate between both groups, a log-rank test with the Kaplan-Meier method was used. The last observation carried forward (LOCF) method was used for missing data (29). Results Patients' characteristics Sixty-five patients (58 women and 7 men) were included in the present study (Table 1). The median (range) age of patients was 69 (61-74) years old, and the median disease duration was 9 (5-16) years. Among the 65 patients, 28 were biologic-naïve (naïve group), and 37 had switched from biologics (switch group). The median (range) follow-up period was 134 (58-162) weeks. MTX was administered in 66% (43/65) of patients at a median (range) dose of 8.0 (0.0-10.0) mg/week. PSL was administered to 65% (42/65) of patients at a median (range) dose of 3.0 (0.0-5.0) mg/day. Other conventional DMARDs (csDMARDs) were used as follows: salazosulfapyridine in 23 cases (naïve/switch=14/9), mizoribine in 19 cases (5/14), bucillamine in 9 cases (3/6), tacrolimus hydrate in 5 cases (1/4), iguratimod in 4 cases (2/2), and actarit in 4 cases (1/3). In the switch group, 31 patients received GLM as the second bDMARD, 5 patients received it as the third bDMARD, and 1 received it as the fifth bDMARD. Moreover, patients in the switch group received infliximab (IFX) (as the first and second bDMARDs: 18, 1 case), etanercept (ETN) (as the first and second bDMARDs: 13, 3 cases), tocilizumab (TCZ) (as the first and third bDMARD: 4, 1 case), abatacept (ABT) (as the first and fourth bDMARD: 1, 1 case), and adalimumab (ADA) (as first and second bDMARD: 1, 2 cases). There was no significant difference in the baseline status between the naïve and switch groups except for with regard to the rheumatoid factor, MTX dose, Steinbrocker Class, and initial dose of GLM (Table 1) (30). Twenty-four patients in the naïve group received 50 mg GLM; the dose was increased to 100 mg in 13 patients. Fourteen patients in the switch group received 50 mg GLM; the dose was increased to 100 mg in 7 patients. The proportion of patients who were administered 100 mg GLM as the initial dose was higher in the switch group (23/37; 62%) than in the naïve group (4/28; 14%; p<0.001). Efficacy results The median (range) DAS28-ESR value was 4.31 (3.52-5.25) in the naïve group and 4.27 (3.19-4.89) in the switch group at baseline (Table 2). At the final follow-up, the median (range) DAS28-ESR value had improved to 2.65 (2.28-3.77) in the naïve group and 2.89 (2.49-3.88) in the switch group. The J-HAQ did not improve in either group. The ratio of low disease activity and remission improved from naïve 18% (5/28)/switch 24% (9/37) at baseline to naïve 60% (15/25)/switch 52% (14/27) at 52 weeks (p<0.05) and naïve 64% (16/25)/switch 67% (18/27) at the final follow-up (p<0.01) (Fig. 1). The median grip power at 52 weeks and at the final follow-up improved in both groups. The MTX and PSL doses were decreased at the final follow-up. The Spearman correlation coefficients of the grip power, J-HAQ, and DAS28-ESR were ρ=-0.426 (grip power vs. J-HAQ), ρ=-0.417 (grip power vs. DAS28-ESR), and ρ=0.348 (J-HAQ vs. DAS28-ESR) (p<0.001). Table 2. The Clinical Course of Golimumab. Week 0 Week 52 Final follow-up Median (range) Median (range) p value Median (range) p value DAS28-ESR Naïve 4.31 (3.52-5.25) 2.76 (2.23-4.05) <0.001 2.65 (2.28-3.77) <0.001* Switch 4.27 (3.19-4.89) 2.69 (2.19-3.78) 0.001* 2.89 (2.49-3.88) 0.006* Total 4.27 (3.35-4.27) 2.73 (2.22-3.90) <0.001* 2.73 (2.35-3.77) <0.001* J-HAQ Naïve 0.25 (0.04-0.71) 0.25 (0.05-1.03) 0.593 0.23 (0.04-0.80) 0.771 Switch 0.48 (0.25-0.85) 0.53 (0.23-0.88) 0.490 0.53 (0.10-0.85) 0.608 Total 0.40 (0.05-0.84) 0.40 (0.07-0.93) 0.552 0.30 (0.10-0.84) 0.761 Grip power, mmHg Naïve 138 (104-183) 160 (102-231) <0.001* 183 (100-234) 0.041* Switch 127 (93-168) 158 (112-195) 0.026* 154 (115-190) <0.001* Total 133 (96-179) 158 (107-204) <0.001* 165(105-208) <0.001* Dose of MTX, mg/week Naïve 8.0 (6.0-10.0) 8.0 (3.0-8.5) 0.006* 5.0 (0.0-8.0) <0.001* Switch 5.0 (0.0-8.5) 6.0 (0.0-9.0) 0.091 6.0 (0.0-8.0) 0.007* Total 8.0 (0.0-10.0) 7.0 (1.3-8.8) 0.003* 5.5 (0.0-8.0) <0.001* Dose of PSL, mg/day Naïve 2.3 (0.0-5.0) 2.0 (0.0-5.0) 0.110 2.0 (0.0-3.8) 0.016* Switch 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.040 2.5 (0.0-4.0) 0.004* Total 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.016* 2.3 (0.0-4.0) <0.001* At 52 weeks and at the final follow-up, each parameter was compared with the baseline value using the Wilcoxon rank sum test adjusted by the Holm method. *: significant difference. Median (range). DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone Figure 1. The DAS28-ESR at baseline, 52 weeks, and the final follow-up. The DAS28-ESR classification improved from baseline to 52 weeks and at the final follow-up in both groups (chi-square test: p<0.05). The classification of DAS28-ESR was as follows: remission, DAS28-ESR<2.6; low disease activity, 2.6≤DAS28-ESR<3.2; moderate disease activity, 3.2≤DAS28-ESR≤5.1; high disease activity, DAS28-ESR>5.1. DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate Continuation rate and reason for discontinuation The continuation rate at the final follow-up [median (range): 134 (58-162) weeks] was 22/28 (78.6%) in the naïve group and 26/37 (70.3%) in the switch group. The respective continuation rates of the naïve/switch/total groups calculated using the Kaplan-Meier method were 89.3%/73.0%/80.0% at 52 weeks, 81.1%/73.0%/76.4% at 104 weeks, and 76.3%/68.7%/71.6% at 156 weeks (Fig. 2). No significant difference was detected in the continuation rate between the naïve and switch groups (p=0.829). The continuation rate in patients who were administered MTX was higher than that in patients who were not administered MTX (p=0.001; Fig. 3). On comparing the backgrounds of the naïve and switch groups, patients without MTX had higher median (range) values for the age, C-reactive protein (CRP), ESR, matrix metalloprotease-3 (MMP-3), and rheumatoid factor (RF) at baseline than those with MTX (p<0.05) [patients without MTX vs. patients with MTX, age 73 (69-78) vs. 65 (54-70), CRP 1.65 (0.25-3.23) vs. 0.40 (0.10-1.50), ESR 45 (23-80) vs. 18 (10-28), MMP-3 171 (87-367) vs. 95 (60-194), RF 83 (33-162) vs. 23 (13-106)]. Seventeen patients discontinued the administration of GLM. The reasons for discontinuation were as follows: lack of efficacy (8/65: 12.3%), infection (3/65: 4.6%), and eczema, multiple sclerosis, economic reasons, patient preference for bDMARDs, fracture, and transfer to another hospital in 1 case each (1/65: 1.5%). Ten patients (1 naïve, 9 switch) discontinued GLM within 26 weeks, and 3 discontinued GLM between 26 and 52 weeks. Five patients discontinued GLM within 26 weeks because of a lack of efficacy. No patients discontinued GLM due to remission. Figure 2. Drug continuation rates in the naïve and switch groups. The drug continuation rate showed no significant difference between both groups (log rank: p=0.829). Figure 3. Drug continuation rates in groups administered GLM with and without MTX. The group administered GLM with MTX showed a better drug continuation rate than the group administered GLM without MTX (log rank: p=0.004). GLM: golimumab, MTX: methotrexate Discussion In this study, evaluated the effectiveness and continuation rate of GLM for long-term use in daily practice for patients with RA. We recorded the clinical effect and the continuation rate of GLM in daily practice after 52 weeks. As hypothesized, GLM showed effectiveness not only in bDMARD-naïve patients but also in switch patients. In our institution, 38 patients started GLM 50 mg; however, 20 increased the dose to 100 mg because the 50-mg regimen was inadequate. Increasing the dose improved the DAS; therefore, if the 50-mg regimen is not effective, increasing the dose should be considered. The GO-AFTER study has also reported the clinical efficacy of switching to GLM therapy (14). In agreement with this finding, we found that GLM therapy was effective even for the switch group patients. The remission rate of the naïve/switch group was 40% (10/25)/41% (11/27) at 52 weeks and 44% (11/25)/33% (9/27) at the final follow-up. In the GO-FORTH and GO-FORWARD trials, the rates of remission based on the DAS28-ESR were 32.4-52.2% at 52 weeks, 39.4-75.8% at 104 weeks, and 55.3-61.8% at 156 weeks (2,5). In 2 previous studies, the average age at the baseline was 50 years old, and the average DAS28-ESR at the baseline was 5.5-5.9; these patients showed better remission rates at 52 and 104 weeks than did our patients (2,5). In our trial, the median age of the recruited patients was 69 years old. Thus, the age and age-related complications might have affected the remission rate in our patients. In the GO-AFTER trial, the remission rate of the bDMARD switch group for 52/100/160 weeks was 12.5-15.6% for the 50 mg regimen and 21.5-22.1% for the 100 mg regimen (3). The switch group in our study showed a better remission rate than that in the GO-AFTER study. The higher the remission rate of the switch group in our study may have been due to the better DAS28-ESR at baseline than in the GO-AFTER study. In the present study, we recruited older patients than those described in previous studies (16,31,32), and we therefore believe that the 65 patients that were collected from a single institution with 134 (58-162) weeks of follow-up thus provided valuable information in comparison to previous studies. The J-HAQ was not improved at the final follow-up compared with that at the baseline in the present study, which was inconsistent with our hypothesis. The HAQ score in healthy populations was reported to be 0.49 (33). The GO-FORWARD, GO-FORTH, GO-AFTER, and GO-MONO trials reported improvements in the HAQ-DI (0.37-0.75), and the HAQ-DI baseline values ranged from 0.9 to 1.6 (6,31,32,34). In these 4 clinical trials, the mean age ranged from 50-55 years old, and the mean DAS28-ESR ranged from 5.5-6.3. The age and DAS28-ESR were higher in our study than in those previous trials. Furthermore, in our study, 17/65 (26%) patients were classified as Steinbrocker stage III and 34/65 (52%) as Steinbrocker stage IV. Despite the low J-HAQ score (0.40) of our case series at the baseline, the number of patients in the different Steinbrocker classes were as follows: 1 in class 1, 35 in class 2, 27 in class 3, and 2 in class 4. The Steinbrocker Stage and Class in our study indicated that most patients had some irreversible ADL impairments. Furthermore, in the present study, the grip power was correlated with the J-HAQ score (ρ=-0.426, p<0.01) and DAS28-ESR (ρ=-0.417, p<0.01). Therefore, we consider it necessary to evaluate the grip power when assessing subclinical joint dysfunction. Consistent with our hypothesis, in the present study, treatment with GLM improved the grip power at 52 weeks and at the final follow-up. The use of GLM not only suppressed joint inflammation but also improved the grip power. Uutela et al. (35) reported that the grip power reflected the disease status, such as remission, low/moderate disease activity, and high disease activity. The present study showed that the grip power was correlated with the J-HAQ and DAS28-ESR as continuous variables. Eberhardt et al. reported that the use of TNF inhibitors for more than one year in patients with RA improved the grip power. However, details concerning the TNF inhibitors were not provided. As their study findings were published in 2007, GLM would not have been used (27). Aside from the abovementioned study by Eberhardt et al., there have been no reports showing improvements in the grip power following the use of TNF inhibitors. Our study is thus the first to show an improvement in the grip power in daily practice following GLM use. Improving the grip power may promote the prevention of sarcopenia and frailty in the future. Therefore, measuring the grip strength will likely provide supplemental information about potential ADL impairment. Only 17 patients (26.1%) discontinued the treatment course in our study, indicating a high continuation rate for long-term GLM use. The ANSWER cohort study, comprising 2,494 patients in real clinical practice, reported the retention rates of the following 7 bDMARDs: ABT (75.5%), TCZ (71.5%), GLM (65.6%), ETN (61.2%), certolizumab pegol (60.7%), ADA (58.2%), and IFX (53.4%) at 36 months in adjusted model (36). A systematic review by Svedbom et al. reported that the continuation rate of GLM was higher than that of other TNF inhibitors (9). An important characteristic of GLM is its lower antigenicity than other bDMARDs (37). The low antibody production against GLM is likely associated with its high continuity. Svedbom et al. showed that the respective continuation rates of GLM in real clinical practice at 52/104/156 weeks were 67-76%/49-63%/60% for bDMARD-naïve patients and 47-63%/40-61%/32-54% for bDMARD-switch patients (9). Kondo et al. reported that the continuation rate of GLM after 6 years was 50.3% (38). Compared with these data from real clinical practice, our study findings showed a better continuation rate of GLM in both the naïve and switch groups. However, the systematic review by Svedbom et al. included abstracts from academic conferences, which may have provided inadequate information. Therefore, it would be difficult to precisely analyze the reason for the difference between our findings and those of the systematic review. In our study, patients discontinued the treatment course due to a lack of efficacy (8/65: 12.3%), toxic effects (5/65: 7.7%), and other reasons (4/65: 6.2%). None of the patients discontinued the treatment due to remission. In the ANSWER cohort study, the drug retention rate of GLM in the adjusted model at 36 months was as follows: lack of effectiveness (74.0%), toxic effect (89.1%), and remission (92.5%) (28). Ten patients discontinued GLM within 26 weeks, and 3 discontinued between 26 and 52 weeks. Five patients discontinued GLM because of a lack of efficacy within 26 weeks. Kondo et al. reported that the discontinuation of the treatment course frequently occurred within six months (38). A steady-state plasma concentration can be achieved with 12 weeks of repeated injection of GLM (39), which is longer than that of other TNF-inhibitors (40). The GO-FORTH trial results showed that concurrent use of MTX leads to earlier disease control at three and six months than GLM monotherapy and switching therapy [based on the American College of Rheumatology criteria (41)] for two to five years (2,14,16). Considering the discontinuation of drug administration within 26 weeks in the present study, we suggest that tight control of the RA status within 26 weeks is necessary until GLM exhibits effectiveness, especially in monotherapy and switching therapy groups. The continuation rate was higher in patients who were administered MTX than in those who were not. Concurrent use of MTX with GLM decreases immunogenicity and adverse events (42). The patients without MTX were older and had higher CRP, ESR, MMP-3, and RF values than the patients with MTX; therefore, older patients and those with more severe inflammation are likely to be more adversely affected by continuation of GLM. According to the EULAR recommendation (17), if MTX is not contraindicated, it should be administered. It was challenging to administer MTX to patients without MTX because of other medical complications. Our data also showed a reduction in PSL use at the final follow-up, suggesting that the use of PSL for the short term soon after GLM induction would facilitate a decrease in disease activity until GLM exhibits effectiveness up to 26 weeks. Introduction of the 100-mg GLM regimen would facilitate the early suppression of disease and prevent early drop-out from treatment. Several limitations associated with the present study warrant mention. This was a retrospective study, and the sample size was smaller than that of clinical trials. Furthermore, the concurrent use of csDMARDs (including MTX and other csDMARDs) differed among the naïve and switch groups. The final selection and dosage of bDMARDs was decided by discussion between the patient and the doctor. The initial dose of GLM was decided while considering not only the patient's disease status but also their economic status. Our study lacks adequate data to explore the risk of discontinuation using a multivariate analysis, as 17 patients discontinued the study. Conclusion GLM improved the disease activity and grip power in bDMARD-naïve and switch groups. The concurrent use of MTX with GLM showed a better continuation rate than GLM administration without MTX. This is the first report to show the improvement in the grip power by GLM and to demonstrate that the use of GLM can prevent sarcopenia in the future. We also found that the grip power was correlated with the J-HAQ and DAS28-ESR. Our findings concerning the effects of GLM may facilitate further studies on effective RA treatment regimens. Author's disclosure of potential Conflicts of Interest (COI). Satoshi Ito: Honoraria, Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Jansen Pharma and Mitsubishi Tanabe. Hajime Ishikawa: Honoraria, Astellas, Chugai, Gilead Sciences and Corrona.	ABATACEPT, ACTARIT, ADALIMUMAB, BUCILLAMINE, ETANERCEPT, GOLIMUMAB, IGURATIMOD, INFLIXIMAB, METHOTREXATE, MIZORIBINE, PREDNISOLONE, SULFASALAZINE, TACROLIMUS, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC-ND	33250460	18,599,924	2021-05-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple sclerosis'.	Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis. Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA. Introduction The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), such as golimumab (GLM), has transformed the treatment of rheumatoid arthritis (RA). GLM is a human monoclonal IgG antibody that binds to tumor necrosis factor-alpha (TNF-α) (1). GLM in combination with methotrexate (MTX) has shown efficacy and safety in phase III clinical trials (2-4). In Japan, the GO-FORTH (5) and GO-MONO (6) trials demonstrated the clinical efficacy and safety of GLM in combination with MTX and as monotherapy, respectively. Based on these data, the Japanese Pharmaceuticals and Medical Devices Agency approved GLM (50 and 100 mg) as the fourth anti-TNF-α antibody in 2011 (7); the 100 mg dose is only available in Japan (8). Sevedbom et al. performed a systematic review to determine the continuation rate of GLM (9). They identified 12 real-world studies; however, only 3 were original articles, whereas the remaining 9 were abstracts from academic conferences (10-12). There have been a few reports of the 100 mg GLM regimen in daily practice administered once every 4 weeks (8,11,13); these reports had follow-up periods of up to 52 weeks. Shono (13) compared the clinical safety and efficacy between a bio-naïve and bio-switch group and reported that the improvement in disease activity was similar between the groups at 24 weeks. Although the GO-FORWARD, GO-AFTER, GO-BEFORE, and GO-MONO studies were randomized controlled trials to show the efficacy and safety of GLM from 120 weeks to 5 years, they differed from studies in real clinical settings (2,14-16). The European League Against Rheumatism (EULAR) has recommended the short-term use of prednisolone (PSL) to control disease activity (17). Since a high dose of PSL has many adverse effects, reducing the dose is useful (18). MTX plays an important role in the treatment of RA, but it also has side effects (19), causing many patients to wish to taper or discontinue MTX therapy (20). Since the introduction of the treat-to-target strategy, patients have sought to achieve a high quality of life (QOL). The Japanese version of the health assessment questionnaire (J-HAQ) is an instrument for measuring the physical function and health-related QOL (21). Sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance” by the Asian Working Group for Sarcopenia in 2014, with a consensus update in 2019 (22). The diagnostic criterion of “low muscle strength” is defined as a grip power <28 kg for men and <18 kg for women. Sarcopenia enhances the fall burden, decreases healthy life expectancy, and increases healthcare costs (23,24). Previous reports on the prevalence of sarcopenia have varied; for example, a meta-analysis showed that the prevalence of sarcopenia in patients with RA was 15-32% (25), and Torii et al. reported a prevalence of 37.1% in Japanese patients (23). In addition, Ishikawa et al. reported that the handgrip power in Japanese patients with RA reflects the level of independence in activity of daily living (ADL), and the cut-off value for independent ADL was 136.5 mmHg (11.8 kgw) for women and 152.5 mmHg (13.5 kgw) for men (26). Only one report has described an improvement in the grip power following the use of bDMARDs, with the use of TNF inhibitors for more than one year being shown to improve the grip power in patients with RA (27). We hypothesized that improving the grip power can not only ameliorate inflammation in the upper extremities in patients with RA but also decrease sarcopenia and increase the healthy life expectancy. We hypothesized that the long-term use of GLM would be safe and effective in bio-naïve and bio-switch patients in real clinical practice and that the use of GLM would facilitate better disease control, reduce the PSL and MTX dosages, and improve the J-HAQ and grip power. Furthermore, we hypothesized that the grip power correlates with the J-HAQ score and Disease Activity Score (DAS) 28-ESR. Therefore, in the present study, we evaluated the effectiveness and drug continuation rate of long-term use of GLM in bDMARD-naïve and switch patients in clinical practice in order to determine the reason for discontinuation because of a lack of efficacy. Materials and Methods We retrospectively analyzed the data of patients with RA administered GLM at Niigata Rheumatic Center from October 2011 to March 2015. Sixty-five patients (58 women and 7 men) started GLM therapy during this period. All patients were followed up for more than 52 weeks. Data were collected in March 2016 and retrospectively analyzed (Table 1). The patients were divided into bDMARD “naïve” and “switch” groups based on their history of use. Table 1. Characteristics of Patients in the Naïve and Switch Groups. Total (n=65) Naïve (n=28) Switch (n=37) p value Female, n (%) 58 (89%) 25 (89%) 33 (89%) 0.990 Age, years 69 (61-74) 68 (60-71) 70 (60-76) 0.180 Disease duration of RA, years 9 (5-16) 10 (2-20) 9 (7-16) 0.418 Follow up period 134 (58-162) 127 (79-148) 142 (80-170) 0.310 Swollen joint count 3 (1-6) 3 (1-6) 2 (0-6) 0.414 Tender joint count 3 (1-6) 4 (1-8) 2 (1-5) 0.149 Patient’s global VAS score, mm 46 (23-59) 47 (25-60) 46 (21-59) 0.842 Doctor’s global VAS score, mm 35 (23-60) 40 (26-60) 35 (19-52) 0.524 ESR, mm/h 23 (12-50) 24 (10-49) 23 (14-50) 0.628 CRP, mg/dL 0.60 (0.10-2.10) 0.40 (0.1-1.8) 0.80 (0.10-2.55) 0.110 RF, IU/mL 47 (18-112) 73 (21-231) 43 (11-99) 0.040* RF, positive (%) 49 (75%) 26 (93%) 23 (62%) 0.003* ACPA, U/mL 88 (22-244) 117 (22-248) 67 (25-213) 0.367 ACPA, positive (%) 57 (87%) 26 (93%) 31 (84%) 0.172 MMP-3, ng/mL 128 (67-214) 93 (62-171) 142 (70-249) 0.161 DAS28-ESR 4.27 (3.35-5.19) 4.31 (3.52-5.25) 4.27 (3.19-4.89) 0.521 J-HAQ 0.40 (0.05-0.84) 0.25 (0.04-0.71) 0.48(0.21-0.88) 0.223 MTX use, n (%) 43 (66%) 22 (79%) 21 (57%) 0.066 Dose of MTX, mg/week 8.0 (0.0-10.0) 8.0 (6.0-10.0) 5.0 (0.0-8.5) 0.046* PSL use, n (%) 42(65%) 16 (57%) 26 (70%) 0.299 Dose of PSL, mg/day 3.0 (0.0-5.0) 2.3 (0.0-5.0) 3.0 (0.0-5.0) 0.299 Steinbrocker Stage (I, II, III, IV) 4:10:17:34 3:5:6:14 1:5:11:20 0.507 Steinbrocker Class (1, 2, 3, 4) 1:35:27:2 1:20:7:0 0:15:20:2 0.030* Initial dose of GLM (50 mg:100 mg) 38:27 24:4 14:23 <0.001** Number of patients with dose escalation, n (%) 20 (31%) 13 (46%) 7 (19%) 0.017* Number of patients who discontinued treatment, n (%) 17 (26%) 6 (21%) 11 (30%) 0.450 P value was calculated by comparing naïve and switch groups. A chi-square test was used for comparison of categorical data between the two groups. The Mann-Whitney U test was used to assess continuous variables of non-paired data. : p<0.05, : p<0.01. Median (range). RA: rheumatoid arthritis, VAS: visual analog scale, ESR: erythrocyte sedimentation rate, CRP: the serum C-reactive protein, RF: rheumatoid factor (positive ≥15), ACPA: anti-cyclic citrullinated peptide antibody (positive ≥4.5), MMP-3: matrix metalloprotease, DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone, Steinbrocker Stage: Classification of the structural state of rheumatoid arthritis (I, II, III, IV), Steinbrocker Class: Classification of the functional state of rheumatoid arthritis (1, 2, 3, 4), GLM: golimumab Informed consent was obtained in the form of an opt-out on a poster. No patients were excluded. Signed informed consent was not required by the ethics committee because this was a retrospective study. This study was performed according to Declaration of Helsinki and was approved by the Niigata Rheumatic Center ethics committee. The diagnosis of RA was based on the 2010 American College of Rheumatology/EULAR classification criteria (28). Patients who had previously used GLM or had congestive heart failure, active tuberculosis, or active infectious diseases were excluded. The GLM induction and dose were decided by discussion between the treating doctor and the patient based on the EULAR recommendations for the management of RA (17). Although 50 mg of GLM is recommended to be used with MTX in Japan (20), we used 50 mg of GLM without MTX for 2 patients in the naïve group and 6 patients in the switch group. GLM was injected subcutaneously every four weeks at the hospital by the medical staff. We evaluated the age, sex, follow-up period, and history of bDMARDs use, MTX use, and corticosteroid use as patients' baseline characteristics. The RA status was evaluated at 0 and 52 weeks and at the final follow-up based on the following: DAS28-ESR, MTX dose, and PSL dose. The grip power and J-HAQ were also assessed to determine the improvement in the ADL (26). The average grip power of both hands was measured using a mercury dynamometer, which was able to measure from 0 to 300 mmHg (28.9 kg). The patients were divided into bDMARD naïve and switch groups and compared with each other. The continuation rate of GLM was compared between the groups. In addition, we compared the continuation rate of GLM in patients who had and had not been administered MTX. The demographic parameters of patients who did and did not use MTX were also compared. Statistical analyses Statistical analyses were performed using the JMPⓇ 14 software program (SAS Institute, Cary, USA). The chi-square test was used for comparisons between two groups for categorical data, while Wilcoxon's signed rank test was used for continuous variables of paired data. In the comparison of continuous variables (baseline vs. 52 weeks and at final follow-up), 13 patients who discontinued GLM treatment before 52 weeks were excluded. The continuous variables at 52 weeks and at the final follow-up were compared with those at baseline by Wilcoxon's signed rank test adjusted using the Holm method. Regarding the Holm method, first, the p values at 52 weeks and at the final follow-up were compared. If the lower of these p values was <0.025 (0.05/2), the difference was considered significant. If the lower of these p values was ≥0.025, then both p values were considered not significant. If the higher of these p value was <0.05, the difference was considered significant. A one-sided Wilcoxon's signed rank test was performed to evaluate the reduction in the DAS28-ESR, J-HAQ, MTX dose, and PSL dose. In addition, Wilcoxon's signed rank test was performed to evaluate the improvement in the grip power. Spearman correlation analysis was performed to determine the correlation of grip power value, J-HAQ, and DAS28-ESR at the baseline, 52 weeks, and the final follow-up. The Mann-Whitney U test was used to assess continuous variables of non-paired data. To compare the drug continuation rate between both groups, a log-rank test with the Kaplan-Meier method was used. The last observation carried forward (LOCF) method was used for missing data (29). Results Patients' characteristics Sixty-five patients (58 women and 7 men) were included in the present study (Table 1). The median (range) age of patients was 69 (61-74) years old, and the median disease duration was 9 (5-16) years. Among the 65 patients, 28 were biologic-naïve (naïve group), and 37 had switched from biologics (switch group). The median (range) follow-up period was 134 (58-162) weeks. MTX was administered in 66% (43/65) of patients at a median (range) dose of 8.0 (0.0-10.0) mg/week. PSL was administered to 65% (42/65) of patients at a median (range) dose of 3.0 (0.0-5.0) mg/day. Other conventional DMARDs (csDMARDs) were used as follows: salazosulfapyridine in 23 cases (naïve/switch=14/9), mizoribine in 19 cases (5/14), bucillamine in 9 cases (3/6), tacrolimus hydrate in 5 cases (1/4), iguratimod in 4 cases (2/2), and actarit in 4 cases (1/3). In the switch group, 31 patients received GLM as the second bDMARD, 5 patients received it as the third bDMARD, and 1 received it as the fifth bDMARD. Moreover, patients in the switch group received infliximab (IFX) (as the first and second bDMARDs: 18, 1 case), etanercept (ETN) (as the first and second bDMARDs: 13, 3 cases), tocilizumab (TCZ) (as the first and third bDMARD: 4, 1 case), abatacept (ABT) (as the first and fourth bDMARD: 1, 1 case), and adalimumab (ADA) (as first and second bDMARD: 1, 2 cases). There was no significant difference in the baseline status between the naïve and switch groups except for with regard to the rheumatoid factor, MTX dose, Steinbrocker Class, and initial dose of GLM (Table 1) (30). Twenty-four patients in the naïve group received 50 mg GLM; the dose was increased to 100 mg in 13 patients. Fourteen patients in the switch group received 50 mg GLM; the dose was increased to 100 mg in 7 patients. The proportion of patients who were administered 100 mg GLM as the initial dose was higher in the switch group (23/37; 62%) than in the naïve group (4/28; 14%; p<0.001). Efficacy results The median (range) DAS28-ESR value was 4.31 (3.52-5.25) in the naïve group and 4.27 (3.19-4.89) in the switch group at baseline (Table 2). At the final follow-up, the median (range) DAS28-ESR value had improved to 2.65 (2.28-3.77) in the naïve group and 2.89 (2.49-3.88) in the switch group. The J-HAQ did not improve in either group. The ratio of low disease activity and remission improved from naïve 18% (5/28)/switch 24% (9/37) at baseline to naïve 60% (15/25)/switch 52% (14/27) at 52 weeks (p<0.05) and naïve 64% (16/25)/switch 67% (18/27) at the final follow-up (p<0.01) (Fig. 1). The median grip power at 52 weeks and at the final follow-up improved in both groups. The MTX and PSL doses were decreased at the final follow-up. The Spearman correlation coefficients of the grip power, J-HAQ, and DAS28-ESR were ρ=-0.426 (grip power vs. J-HAQ), ρ=-0.417 (grip power vs. DAS28-ESR), and ρ=0.348 (J-HAQ vs. DAS28-ESR) (p<0.001). Table 2. The Clinical Course of Golimumab. Week 0 Week 52 Final follow-up Median (range) Median (range) p value Median (range) p value DAS28-ESR Naïve 4.31 (3.52-5.25) 2.76 (2.23-4.05) <0.001 2.65 (2.28-3.77) <0.001* Switch 4.27 (3.19-4.89) 2.69 (2.19-3.78) 0.001* 2.89 (2.49-3.88) 0.006* Total 4.27 (3.35-4.27) 2.73 (2.22-3.90) <0.001* 2.73 (2.35-3.77) <0.001* J-HAQ Naïve 0.25 (0.04-0.71) 0.25 (0.05-1.03) 0.593 0.23 (0.04-0.80) 0.771 Switch 0.48 (0.25-0.85) 0.53 (0.23-0.88) 0.490 0.53 (0.10-0.85) 0.608 Total 0.40 (0.05-0.84) 0.40 (0.07-0.93) 0.552 0.30 (0.10-0.84) 0.761 Grip power, mmHg Naïve 138 (104-183) 160 (102-231) <0.001* 183 (100-234) 0.041* Switch 127 (93-168) 158 (112-195) 0.026* 154 (115-190) <0.001* Total 133 (96-179) 158 (107-204) <0.001* 165(105-208) <0.001* Dose of MTX, mg/week Naïve 8.0 (6.0-10.0) 8.0 (3.0-8.5) 0.006* 5.0 (0.0-8.0) <0.001* Switch 5.0 (0.0-8.5) 6.0 (0.0-9.0) 0.091 6.0 (0.0-8.0) 0.007* Total 8.0 (0.0-10.0) 7.0 (1.3-8.8) 0.003* 5.5 (0.0-8.0) <0.001* Dose of PSL, mg/day Naïve 2.3 (0.0-5.0) 2.0 (0.0-5.0) 0.110 2.0 (0.0-3.8) 0.016* Switch 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.040 2.5 (0.0-4.0) 0.004* Total 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.016* 2.3 (0.0-4.0) <0.001* At 52 weeks and at the final follow-up, each parameter was compared with the baseline value using the Wilcoxon rank sum test adjusted by the Holm method. *: significant difference. Median (range). DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone Figure 1. The DAS28-ESR at baseline, 52 weeks, and the final follow-up. The DAS28-ESR classification improved from baseline to 52 weeks and at the final follow-up in both groups (chi-square test: p<0.05). The classification of DAS28-ESR was as follows: remission, DAS28-ESR<2.6; low disease activity, 2.6≤DAS28-ESR<3.2; moderate disease activity, 3.2≤DAS28-ESR≤5.1; high disease activity, DAS28-ESR>5.1. DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate Continuation rate and reason for discontinuation The continuation rate at the final follow-up [median (range): 134 (58-162) weeks] was 22/28 (78.6%) in the naïve group and 26/37 (70.3%) in the switch group. The respective continuation rates of the naïve/switch/total groups calculated using the Kaplan-Meier method were 89.3%/73.0%/80.0% at 52 weeks, 81.1%/73.0%/76.4% at 104 weeks, and 76.3%/68.7%/71.6% at 156 weeks (Fig. 2). No significant difference was detected in the continuation rate between the naïve and switch groups (p=0.829). The continuation rate in patients who were administered MTX was higher than that in patients who were not administered MTX (p=0.001; Fig. 3). On comparing the backgrounds of the naïve and switch groups, patients without MTX had higher median (range) values for the age, C-reactive protein (CRP), ESR, matrix metalloprotease-3 (MMP-3), and rheumatoid factor (RF) at baseline than those with MTX (p<0.05) [patients without MTX vs. patients with MTX, age 73 (69-78) vs. 65 (54-70), CRP 1.65 (0.25-3.23) vs. 0.40 (0.10-1.50), ESR 45 (23-80) vs. 18 (10-28), MMP-3 171 (87-367) vs. 95 (60-194), RF 83 (33-162) vs. 23 (13-106)]. Seventeen patients discontinued the administration of GLM. The reasons for discontinuation were as follows: lack of efficacy (8/65: 12.3%), infection (3/65: 4.6%), and eczema, multiple sclerosis, economic reasons, patient preference for bDMARDs, fracture, and transfer to another hospital in 1 case each (1/65: 1.5%). Ten patients (1 naïve, 9 switch) discontinued GLM within 26 weeks, and 3 discontinued GLM between 26 and 52 weeks. Five patients discontinued GLM within 26 weeks because of a lack of efficacy. No patients discontinued GLM due to remission. Figure 2. Drug continuation rates in the naïve and switch groups. The drug continuation rate showed no significant difference between both groups (log rank: p=0.829). Figure 3. Drug continuation rates in groups administered GLM with and without MTX. The group administered GLM with MTX showed a better drug continuation rate than the group administered GLM without MTX (log rank: p=0.004). GLM: golimumab, MTX: methotrexate Discussion In this study, evaluated the effectiveness and continuation rate of GLM for long-term use in daily practice for patients with RA. We recorded the clinical effect and the continuation rate of GLM in daily practice after 52 weeks. As hypothesized, GLM showed effectiveness not only in bDMARD-naïve patients but also in switch patients. In our institution, 38 patients started GLM 50 mg; however, 20 increased the dose to 100 mg because the 50-mg regimen was inadequate. Increasing the dose improved the DAS; therefore, if the 50-mg regimen is not effective, increasing the dose should be considered. The GO-AFTER study has also reported the clinical efficacy of switching to GLM therapy (14). In agreement with this finding, we found that GLM therapy was effective even for the switch group patients. The remission rate of the naïve/switch group was 40% (10/25)/41% (11/27) at 52 weeks and 44% (11/25)/33% (9/27) at the final follow-up. In the GO-FORTH and GO-FORWARD trials, the rates of remission based on the DAS28-ESR were 32.4-52.2% at 52 weeks, 39.4-75.8% at 104 weeks, and 55.3-61.8% at 156 weeks (2,5). In 2 previous studies, the average age at the baseline was 50 years old, and the average DAS28-ESR at the baseline was 5.5-5.9; these patients showed better remission rates at 52 and 104 weeks than did our patients (2,5). In our trial, the median age of the recruited patients was 69 years old. Thus, the age and age-related complications might have affected the remission rate in our patients. In the GO-AFTER trial, the remission rate of the bDMARD switch group for 52/100/160 weeks was 12.5-15.6% for the 50 mg regimen and 21.5-22.1% for the 100 mg regimen (3). The switch group in our study showed a better remission rate than that in the GO-AFTER study. The higher the remission rate of the switch group in our study may have been due to the better DAS28-ESR at baseline than in the GO-AFTER study. In the present study, we recruited older patients than those described in previous studies (16,31,32), and we therefore believe that the 65 patients that were collected from a single institution with 134 (58-162) weeks of follow-up thus provided valuable information in comparison to previous studies. The J-HAQ was not improved at the final follow-up compared with that at the baseline in the present study, which was inconsistent with our hypothesis. The HAQ score in healthy populations was reported to be 0.49 (33). The GO-FORWARD, GO-FORTH, GO-AFTER, and GO-MONO trials reported improvements in the HAQ-DI (0.37-0.75), and the HAQ-DI baseline values ranged from 0.9 to 1.6 (6,31,32,34). In these 4 clinical trials, the mean age ranged from 50-55 years old, and the mean DAS28-ESR ranged from 5.5-6.3. The age and DAS28-ESR were higher in our study than in those previous trials. Furthermore, in our study, 17/65 (26%) patients were classified as Steinbrocker stage III and 34/65 (52%) as Steinbrocker stage IV. Despite the low J-HAQ score (0.40) of our case series at the baseline, the number of patients in the different Steinbrocker classes were as follows: 1 in class 1, 35 in class 2, 27 in class 3, and 2 in class 4. The Steinbrocker Stage and Class in our study indicated that most patients had some irreversible ADL impairments. Furthermore, in the present study, the grip power was correlated with the J-HAQ score (ρ=-0.426, p<0.01) and DAS28-ESR (ρ=-0.417, p<0.01). Therefore, we consider it necessary to evaluate the grip power when assessing subclinical joint dysfunction. Consistent with our hypothesis, in the present study, treatment with GLM improved the grip power at 52 weeks and at the final follow-up. The use of GLM not only suppressed joint inflammation but also improved the grip power. Uutela et al. (35) reported that the grip power reflected the disease status, such as remission, low/moderate disease activity, and high disease activity. The present study showed that the grip power was correlated with the J-HAQ and DAS28-ESR as continuous variables. Eberhardt et al. reported that the use of TNF inhibitors for more than one year in patients with RA improved the grip power. However, details concerning the TNF inhibitors were not provided. As their study findings were published in 2007, GLM would not have been used (27). Aside from the abovementioned study by Eberhardt et al., there have been no reports showing improvements in the grip power following the use of TNF inhibitors. Our study is thus the first to show an improvement in the grip power in daily practice following GLM use. Improving the grip power may promote the prevention of sarcopenia and frailty in the future. Therefore, measuring the grip strength will likely provide supplemental information about potential ADL impairment. Only 17 patients (26.1%) discontinued the treatment course in our study, indicating a high continuation rate for long-term GLM use. The ANSWER cohort study, comprising 2,494 patients in real clinical practice, reported the retention rates of the following 7 bDMARDs: ABT (75.5%), TCZ (71.5%), GLM (65.6%), ETN (61.2%), certolizumab pegol (60.7%), ADA (58.2%), and IFX (53.4%) at 36 months in adjusted model (36). A systematic review by Svedbom et al. reported that the continuation rate of GLM was higher than that of other TNF inhibitors (9). An important characteristic of GLM is its lower antigenicity than other bDMARDs (37). The low antibody production against GLM is likely associated with its high continuity. Svedbom et al. showed that the respective continuation rates of GLM in real clinical practice at 52/104/156 weeks were 67-76%/49-63%/60% for bDMARD-naïve patients and 47-63%/40-61%/32-54% for bDMARD-switch patients (9). Kondo et al. reported that the continuation rate of GLM after 6 years was 50.3% (38). Compared with these data from real clinical practice, our study findings showed a better continuation rate of GLM in both the naïve and switch groups. However, the systematic review by Svedbom et al. included abstracts from academic conferences, which may have provided inadequate information. Therefore, it would be difficult to precisely analyze the reason for the difference between our findings and those of the systematic review. In our study, patients discontinued the treatment course due to a lack of efficacy (8/65: 12.3%), toxic effects (5/65: 7.7%), and other reasons (4/65: 6.2%). None of the patients discontinued the treatment due to remission. In the ANSWER cohort study, the drug retention rate of GLM in the adjusted model at 36 months was as follows: lack of effectiveness (74.0%), toxic effect (89.1%), and remission (92.5%) (28). Ten patients discontinued GLM within 26 weeks, and 3 discontinued between 26 and 52 weeks. Five patients discontinued GLM because of a lack of efficacy within 26 weeks. Kondo et al. reported that the discontinuation of the treatment course frequently occurred within six months (38). A steady-state plasma concentration can be achieved with 12 weeks of repeated injection of GLM (39), which is longer than that of other TNF-inhibitors (40). The GO-FORTH trial results showed that concurrent use of MTX leads to earlier disease control at three and six months than GLM monotherapy and switching therapy [based on the American College of Rheumatology criteria (41)] for two to five years (2,14,16). Considering the discontinuation of drug administration within 26 weeks in the present study, we suggest that tight control of the RA status within 26 weeks is necessary until GLM exhibits effectiveness, especially in monotherapy and switching therapy groups. The continuation rate was higher in patients who were administered MTX than in those who were not. Concurrent use of MTX with GLM decreases immunogenicity and adverse events (42). The patients without MTX were older and had higher CRP, ESR, MMP-3, and RF values than the patients with MTX; therefore, older patients and those with more severe inflammation are likely to be more adversely affected by continuation of GLM. According to the EULAR recommendation (17), if MTX is not contraindicated, it should be administered. It was challenging to administer MTX to patients without MTX because of other medical complications. Our data also showed a reduction in PSL use at the final follow-up, suggesting that the use of PSL for the short term soon after GLM induction would facilitate a decrease in disease activity until GLM exhibits effectiveness up to 26 weeks. Introduction of the 100-mg GLM regimen would facilitate the early suppression of disease and prevent early drop-out from treatment. Several limitations associated with the present study warrant mention. This was a retrospective study, and the sample size was smaller than that of clinical trials. Furthermore, the concurrent use of csDMARDs (including MTX and other csDMARDs) differed among the naïve and switch groups. The final selection and dosage of bDMARDs was decided by discussion between the patient and the doctor. The initial dose of GLM was decided while considering not only the patient's disease status but also their economic status. Our study lacks adequate data to explore the risk of discontinuation using a multivariate analysis, as 17 patients discontinued the study. Conclusion GLM improved the disease activity and grip power in bDMARD-naïve and switch groups. The concurrent use of MTX with GLM showed a better continuation rate than GLM administration without MTX. This is the first report to show the improvement in the grip power by GLM and to demonstrate that the use of GLM can prevent sarcopenia in the future. We also found that the grip power was correlated with the J-HAQ and DAS28-ESR. Our findings concerning the effects of GLM may facilitate further studies on effective RA treatment regimens. Author's disclosure of potential Conflicts of Interest (COI). Satoshi Ito: Honoraria, Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Jansen Pharma and Mitsubishi Tanabe. Hajime Ishikawa: Honoraria, Astellas, Chugai, Gilead Sciences and Corrona.	ABATACEPT, ACTARIT, ADALIMUMAB, BUCILLAMINE, ETANERCEPT, GOLIMUMAB, IGURATIMOD, INFLIXIMAB, METHOTREXATE, MIZORIBINE, PREDNISOLONE, SULFASALAZINE, TACROLIMUS, TOCILIZUMAB	DrugsGivenReaction	CC BY-NC-ND	33250460	18,599,924	2021-05-01
What was the administration route of drug 'GOLIMUMAB'?	Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis. Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA. Introduction The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), such as golimumab (GLM), has transformed the treatment of rheumatoid arthritis (RA). GLM is a human monoclonal IgG antibody that binds to tumor necrosis factor-alpha (TNF-α) (1). GLM in combination with methotrexate (MTX) has shown efficacy and safety in phase III clinical trials (2-4). In Japan, the GO-FORTH (5) and GO-MONO (6) trials demonstrated the clinical efficacy and safety of GLM in combination with MTX and as monotherapy, respectively. Based on these data, the Japanese Pharmaceuticals and Medical Devices Agency approved GLM (50 and 100 mg) as the fourth anti-TNF-α antibody in 2011 (7); the 100 mg dose is only available in Japan (8). Sevedbom et al. performed a systematic review to determine the continuation rate of GLM (9). They identified 12 real-world studies; however, only 3 were original articles, whereas the remaining 9 were abstracts from academic conferences (10-12). There have been a few reports of the 100 mg GLM regimen in daily practice administered once every 4 weeks (8,11,13); these reports had follow-up periods of up to 52 weeks. Shono (13) compared the clinical safety and efficacy between a bio-naïve and bio-switch group and reported that the improvement in disease activity was similar between the groups at 24 weeks. Although the GO-FORWARD, GO-AFTER, GO-BEFORE, and GO-MONO studies were randomized controlled trials to show the efficacy and safety of GLM from 120 weeks to 5 years, they differed from studies in real clinical settings (2,14-16). The European League Against Rheumatism (EULAR) has recommended the short-term use of prednisolone (PSL) to control disease activity (17). Since a high dose of PSL has many adverse effects, reducing the dose is useful (18). MTX plays an important role in the treatment of RA, but it also has side effects (19), causing many patients to wish to taper or discontinue MTX therapy (20). Since the introduction of the treat-to-target strategy, patients have sought to achieve a high quality of life (QOL). The Japanese version of the health assessment questionnaire (J-HAQ) is an instrument for measuring the physical function and health-related QOL (21). Sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance” by the Asian Working Group for Sarcopenia in 2014, with a consensus update in 2019 (22). The diagnostic criterion of “low muscle strength” is defined as a grip power <28 kg for men and <18 kg for women. Sarcopenia enhances the fall burden, decreases healthy life expectancy, and increases healthcare costs (23,24). Previous reports on the prevalence of sarcopenia have varied; for example, a meta-analysis showed that the prevalence of sarcopenia in patients with RA was 15-32% (25), and Torii et al. reported a prevalence of 37.1% in Japanese patients (23). In addition, Ishikawa et al. reported that the handgrip power in Japanese patients with RA reflects the level of independence in activity of daily living (ADL), and the cut-off value for independent ADL was 136.5 mmHg (11.8 kgw) for women and 152.5 mmHg (13.5 kgw) for men (26). Only one report has described an improvement in the grip power following the use of bDMARDs, with the use of TNF inhibitors for more than one year being shown to improve the grip power in patients with RA (27). We hypothesized that improving the grip power can not only ameliorate inflammation in the upper extremities in patients with RA but also decrease sarcopenia and increase the healthy life expectancy. We hypothesized that the long-term use of GLM would be safe and effective in bio-naïve and bio-switch patients in real clinical practice and that the use of GLM would facilitate better disease control, reduce the PSL and MTX dosages, and improve the J-HAQ and grip power. Furthermore, we hypothesized that the grip power correlates with the J-HAQ score and Disease Activity Score (DAS) 28-ESR. Therefore, in the present study, we evaluated the effectiveness and drug continuation rate of long-term use of GLM in bDMARD-naïve and switch patients in clinical practice in order to determine the reason for discontinuation because of a lack of efficacy. Materials and Methods We retrospectively analyzed the data of patients with RA administered GLM at Niigata Rheumatic Center from October 2011 to March 2015. Sixty-five patients (58 women and 7 men) started GLM therapy during this period. All patients were followed up for more than 52 weeks. Data were collected in March 2016 and retrospectively analyzed (Table 1). The patients were divided into bDMARD “naïve” and “switch” groups based on their history of use. Table 1. Characteristics of Patients in the Naïve and Switch Groups. Total (n=65) Naïve (n=28) Switch (n=37) p value Female, n (%) 58 (89%) 25 (89%) 33 (89%) 0.990 Age, years 69 (61-74) 68 (60-71) 70 (60-76) 0.180 Disease duration of RA, years 9 (5-16) 10 (2-20) 9 (7-16) 0.418 Follow up period 134 (58-162) 127 (79-148) 142 (80-170) 0.310 Swollen joint count 3 (1-6) 3 (1-6) 2 (0-6) 0.414 Tender joint count 3 (1-6) 4 (1-8) 2 (1-5) 0.149 Patient’s global VAS score, mm 46 (23-59) 47 (25-60) 46 (21-59) 0.842 Doctor’s global VAS score, mm 35 (23-60) 40 (26-60) 35 (19-52) 0.524 ESR, mm/h 23 (12-50) 24 (10-49) 23 (14-50) 0.628 CRP, mg/dL 0.60 (0.10-2.10) 0.40 (0.1-1.8) 0.80 (0.10-2.55) 0.110 RF, IU/mL 47 (18-112) 73 (21-231) 43 (11-99) 0.040* RF, positive (%) 49 (75%) 26 (93%) 23 (62%) 0.003* ACPA, U/mL 88 (22-244) 117 (22-248) 67 (25-213) 0.367 ACPA, positive (%) 57 (87%) 26 (93%) 31 (84%) 0.172 MMP-3, ng/mL 128 (67-214) 93 (62-171) 142 (70-249) 0.161 DAS28-ESR 4.27 (3.35-5.19) 4.31 (3.52-5.25) 4.27 (3.19-4.89) 0.521 J-HAQ 0.40 (0.05-0.84) 0.25 (0.04-0.71) 0.48(0.21-0.88) 0.223 MTX use, n (%) 43 (66%) 22 (79%) 21 (57%) 0.066 Dose of MTX, mg/week 8.0 (0.0-10.0) 8.0 (6.0-10.0) 5.0 (0.0-8.5) 0.046* PSL use, n (%) 42(65%) 16 (57%) 26 (70%) 0.299 Dose of PSL, mg/day 3.0 (0.0-5.0) 2.3 (0.0-5.0) 3.0 (0.0-5.0) 0.299 Steinbrocker Stage (I, II, III, IV) 4:10:17:34 3:5:6:14 1:5:11:20 0.507 Steinbrocker Class (1, 2, 3, 4) 1:35:27:2 1:20:7:0 0:15:20:2 0.030* Initial dose of GLM (50 mg:100 mg) 38:27 24:4 14:23 <0.001** Number of patients with dose escalation, n (%) 20 (31%) 13 (46%) 7 (19%) 0.017* Number of patients who discontinued treatment, n (%) 17 (26%) 6 (21%) 11 (30%) 0.450 P value was calculated by comparing naïve and switch groups. A chi-square test was used for comparison of categorical data between the two groups. The Mann-Whitney U test was used to assess continuous variables of non-paired data. : p<0.05, : p<0.01. Median (range). RA: rheumatoid arthritis, VAS: visual analog scale, ESR: erythrocyte sedimentation rate, CRP: the serum C-reactive protein, RF: rheumatoid factor (positive ≥15), ACPA: anti-cyclic citrullinated peptide antibody (positive ≥4.5), MMP-3: matrix metalloprotease, DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone, Steinbrocker Stage: Classification of the structural state of rheumatoid arthritis (I, II, III, IV), Steinbrocker Class: Classification of the functional state of rheumatoid arthritis (1, 2, 3, 4), GLM: golimumab Informed consent was obtained in the form of an opt-out on a poster. No patients were excluded. Signed informed consent was not required by the ethics committee because this was a retrospective study. This study was performed according to Declaration of Helsinki and was approved by the Niigata Rheumatic Center ethics committee. The diagnosis of RA was based on the 2010 American College of Rheumatology/EULAR classification criteria (28). Patients who had previously used GLM or had congestive heart failure, active tuberculosis, or active infectious diseases were excluded. The GLM induction and dose were decided by discussion between the treating doctor and the patient based on the EULAR recommendations for the management of RA (17). Although 50 mg of GLM is recommended to be used with MTX in Japan (20), we used 50 mg of GLM without MTX for 2 patients in the naïve group and 6 patients in the switch group. GLM was injected subcutaneously every four weeks at the hospital by the medical staff. We evaluated the age, sex, follow-up period, and history of bDMARDs use, MTX use, and corticosteroid use as patients' baseline characteristics. The RA status was evaluated at 0 and 52 weeks and at the final follow-up based on the following: DAS28-ESR, MTX dose, and PSL dose. The grip power and J-HAQ were also assessed to determine the improvement in the ADL (26). The average grip power of both hands was measured using a mercury dynamometer, which was able to measure from 0 to 300 mmHg (28.9 kg). The patients were divided into bDMARD naïve and switch groups and compared with each other. The continuation rate of GLM was compared between the groups. In addition, we compared the continuation rate of GLM in patients who had and had not been administered MTX. The demographic parameters of patients who did and did not use MTX were also compared. Statistical analyses Statistical analyses were performed using the JMPⓇ 14 software program (SAS Institute, Cary, USA). The chi-square test was used for comparisons between two groups for categorical data, while Wilcoxon's signed rank test was used for continuous variables of paired data. In the comparison of continuous variables (baseline vs. 52 weeks and at final follow-up), 13 patients who discontinued GLM treatment before 52 weeks were excluded. The continuous variables at 52 weeks and at the final follow-up were compared with those at baseline by Wilcoxon's signed rank test adjusted using the Holm method. Regarding the Holm method, first, the p values at 52 weeks and at the final follow-up were compared. If the lower of these p values was <0.025 (0.05/2), the difference was considered significant. If the lower of these p values was ≥0.025, then both p values were considered not significant. If the higher of these p value was <0.05, the difference was considered significant. A one-sided Wilcoxon's signed rank test was performed to evaluate the reduction in the DAS28-ESR, J-HAQ, MTX dose, and PSL dose. In addition, Wilcoxon's signed rank test was performed to evaluate the improvement in the grip power. Spearman correlation analysis was performed to determine the correlation of grip power value, J-HAQ, and DAS28-ESR at the baseline, 52 weeks, and the final follow-up. The Mann-Whitney U test was used to assess continuous variables of non-paired data. To compare the drug continuation rate between both groups, a log-rank test with the Kaplan-Meier method was used. The last observation carried forward (LOCF) method was used for missing data (29). Results Patients' characteristics Sixty-five patients (58 women and 7 men) were included in the present study (Table 1). The median (range) age of patients was 69 (61-74) years old, and the median disease duration was 9 (5-16) years. Among the 65 patients, 28 were biologic-naïve (naïve group), and 37 had switched from biologics (switch group). The median (range) follow-up period was 134 (58-162) weeks. MTX was administered in 66% (43/65) of patients at a median (range) dose of 8.0 (0.0-10.0) mg/week. PSL was administered to 65% (42/65) of patients at a median (range) dose of 3.0 (0.0-5.0) mg/day. Other conventional DMARDs (csDMARDs) were used as follows: salazosulfapyridine in 23 cases (naïve/switch=14/9), mizoribine in 19 cases (5/14), bucillamine in 9 cases (3/6), tacrolimus hydrate in 5 cases (1/4), iguratimod in 4 cases (2/2), and actarit in 4 cases (1/3). In the switch group, 31 patients received GLM as the second bDMARD, 5 patients received it as the third bDMARD, and 1 received it as the fifth bDMARD. Moreover, patients in the switch group received infliximab (IFX) (as the first and second bDMARDs: 18, 1 case), etanercept (ETN) (as the first and second bDMARDs: 13, 3 cases), tocilizumab (TCZ) (as the first and third bDMARD: 4, 1 case), abatacept (ABT) (as the first and fourth bDMARD: 1, 1 case), and adalimumab (ADA) (as first and second bDMARD: 1, 2 cases). There was no significant difference in the baseline status between the naïve and switch groups except for with regard to the rheumatoid factor, MTX dose, Steinbrocker Class, and initial dose of GLM (Table 1) (30). Twenty-four patients in the naïve group received 50 mg GLM; the dose was increased to 100 mg in 13 patients. Fourteen patients in the switch group received 50 mg GLM; the dose was increased to 100 mg in 7 patients. The proportion of patients who were administered 100 mg GLM as the initial dose was higher in the switch group (23/37; 62%) than in the naïve group (4/28; 14%; p<0.001). Efficacy results The median (range) DAS28-ESR value was 4.31 (3.52-5.25) in the naïve group and 4.27 (3.19-4.89) in the switch group at baseline (Table 2). At the final follow-up, the median (range) DAS28-ESR value had improved to 2.65 (2.28-3.77) in the naïve group and 2.89 (2.49-3.88) in the switch group. The J-HAQ did not improve in either group. The ratio of low disease activity and remission improved from naïve 18% (5/28)/switch 24% (9/37) at baseline to naïve 60% (15/25)/switch 52% (14/27) at 52 weeks (p<0.05) and naïve 64% (16/25)/switch 67% (18/27) at the final follow-up (p<0.01) (Fig. 1). The median grip power at 52 weeks and at the final follow-up improved in both groups. The MTX and PSL doses were decreased at the final follow-up. The Spearman correlation coefficients of the grip power, J-HAQ, and DAS28-ESR were ρ=-0.426 (grip power vs. J-HAQ), ρ=-0.417 (grip power vs. DAS28-ESR), and ρ=0.348 (J-HAQ vs. DAS28-ESR) (p<0.001). Table 2. The Clinical Course of Golimumab. Week 0 Week 52 Final follow-up Median (range) Median (range) p value Median (range) p value DAS28-ESR Naïve 4.31 (3.52-5.25) 2.76 (2.23-4.05) <0.001 2.65 (2.28-3.77) <0.001* Switch 4.27 (3.19-4.89) 2.69 (2.19-3.78) 0.001* 2.89 (2.49-3.88) 0.006* Total 4.27 (3.35-4.27) 2.73 (2.22-3.90) <0.001* 2.73 (2.35-3.77) <0.001* J-HAQ Naïve 0.25 (0.04-0.71) 0.25 (0.05-1.03) 0.593 0.23 (0.04-0.80) 0.771 Switch 0.48 (0.25-0.85) 0.53 (0.23-0.88) 0.490 0.53 (0.10-0.85) 0.608 Total 0.40 (0.05-0.84) 0.40 (0.07-0.93) 0.552 0.30 (0.10-0.84) 0.761 Grip power, mmHg Naïve 138 (104-183) 160 (102-231) <0.001* 183 (100-234) 0.041* Switch 127 (93-168) 158 (112-195) 0.026* 154 (115-190) <0.001* Total 133 (96-179) 158 (107-204) <0.001* 165(105-208) <0.001* Dose of MTX, mg/week Naïve 8.0 (6.0-10.0) 8.0 (3.0-8.5) 0.006* 5.0 (0.0-8.0) <0.001* Switch 5.0 (0.0-8.5) 6.0 (0.0-9.0) 0.091 6.0 (0.0-8.0) 0.007* Total 8.0 (0.0-10.0) 7.0 (1.3-8.8) 0.003* 5.5 (0.0-8.0) <0.001* Dose of PSL, mg/day Naïve 2.3 (0.0-5.0) 2.0 (0.0-5.0) 0.110 2.0 (0.0-3.8) 0.016* Switch 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.040 2.5 (0.0-4.0) 0.004* Total 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.016* 2.3 (0.0-4.0) <0.001* At 52 weeks and at the final follow-up, each parameter was compared with the baseline value using the Wilcoxon rank sum test adjusted by the Holm method. *: significant difference. Median (range). DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone Figure 1. The DAS28-ESR at baseline, 52 weeks, and the final follow-up. The DAS28-ESR classification improved from baseline to 52 weeks and at the final follow-up in both groups (chi-square test: p<0.05). The classification of DAS28-ESR was as follows: remission, DAS28-ESR<2.6; low disease activity, 2.6≤DAS28-ESR<3.2; moderate disease activity, 3.2≤DAS28-ESR≤5.1; high disease activity, DAS28-ESR>5.1. DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate Continuation rate and reason for discontinuation The continuation rate at the final follow-up [median (range): 134 (58-162) weeks] was 22/28 (78.6%) in the naïve group and 26/37 (70.3%) in the switch group. The respective continuation rates of the naïve/switch/total groups calculated using the Kaplan-Meier method were 89.3%/73.0%/80.0% at 52 weeks, 81.1%/73.0%/76.4% at 104 weeks, and 76.3%/68.7%/71.6% at 156 weeks (Fig. 2). No significant difference was detected in the continuation rate between the naïve and switch groups (p=0.829). The continuation rate in patients who were administered MTX was higher than that in patients who were not administered MTX (p=0.001; Fig. 3). On comparing the backgrounds of the naïve and switch groups, patients without MTX had higher median (range) values for the age, C-reactive protein (CRP), ESR, matrix metalloprotease-3 (MMP-3), and rheumatoid factor (RF) at baseline than those with MTX (p<0.05) [patients without MTX vs. patients with MTX, age 73 (69-78) vs. 65 (54-70), CRP 1.65 (0.25-3.23) vs. 0.40 (0.10-1.50), ESR 45 (23-80) vs. 18 (10-28), MMP-3 171 (87-367) vs. 95 (60-194), RF 83 (33-162) vs. 23 (13-106)]. Seventeen patients discontinued the administration of GLM. The reasons for discontinuation were as follows: lack of efficacy (8/65: 12.3%), infection (3/65: 4.6%), and eczema, multiple sclerosis, economic reasons, patient preference for bDMARDs, fracture, and transfer to another hospital in 1 case each (1/65: 1.5%). Ten patients (1 naïve, 9 switch) discontinued GLM within 26 weeks, and 3 discontinued GLM between 26 and 52 weeks. Five patients discontinued GLM within 26 weeks because of a lack of efficacy. No patients discontinued GLM due to remission. Figure 2. Drug continuation rates in the naïve and switch groups. The drug continuation rate showed no significant difference between both groups (log rank: p=0.829). Figure 3. Drug continuation rates in groups administered GLM with and without MTX. The group administered GLM with MTX showed a better drug continuation rate than the group administered GLM without MTX (log rank: p=0.004). GLM: golimumab, MTX: methotrexate Discussion In this study, evaluated the effectiveness and continuation rate of GLM for long-term use in daily practice for patients with RA. We recorded the clinical effect and the continuation rate of GLM in daily practice after 52 weeks. As hypothesized, GLM showed effectiveness not only in bDMARD-naïve patients but also in switch patients. In our institution, 38 patients started GLM 50 mg; however, 20 increased the dose to 100 mg because the 50-mg regimen was inadequate. Increasing the dose improved the DAS; therefore, if the 50-mg regimen is not effective, increasing the dose should be considered. The GO-AFTER study has also reported the clinical efficacy of switching to GLM therapy (14). In agreement with this finding, we found that GLM therapy was effective even for the switch group patients. The remission rate of the naïve/switch group was 40% (10/25)/41% (11/27) at 52 weeks and 44% (11/25)/33% (9/27) at the final follow-up. In the GO-FORTH and GO-FORWARD trials, the rates of remission based on the DAS28-ESR were 32.4-52.2% at 52 weeks, 39.4-75.8% at 104 weeks, and 55.3-61.8% at 156 weeks (2,5). In 2 previous studies, the average age at the baseline was 50 years old, and the average DAS28-ESR at the baseline was 5.5-5.9; these patients showed better remission rates at 52 and 104 weeks than did our patients (2,5). In our trial, the median age of the recruited patients was 69 years old. Thus, the age and age-related complications might have affected the remission rate in our patients. In the GO-AFTER trial, the remission rate of the bDMARD switch group for 52/100/160 weeks was 12.5-15.6% for the 50 mg regimen and 21.5-22.1% for the 100 mg regimen (3). The switch group in our study showed a better remission rate than that in the GO-AFTER study. The higher the remission rate of the switch group in our study may have been due to the better DAS28-ESR at baseline than in the GO-AFTER study. In the present study, we recruited older patients than those described in previous studies (16,31,32), and we therefore believe that the 65 patients that were collected from a single institution with 134 (58-162) weeks of follow-up thus provided valuable information in comparison to previous studies. The J-HAQ was not improved at the final follow-up compared with that at the baseline in the present study, which was inconsistent with our hypothesis. The HAQ score in healthy populations was reported to be 0.49 (33). The GO-FORWARD, GO-FORTH, GO-AFTER, and GO-MONO trials reported improvements in the HAQ-DI (0.37-0.75), and the HAQ-DI baseline values ranged from 0.9 to 1.6 (6,31,32,34). In these 4 clinical trials, the mean age ranged from 50-55 years old, and the mean DAS28-ESR ranged from 5.5-6.3. The age and DAS28-ESR were higher in our study than in those previous trials. Furthermore, in our study, 17/65 (26%) patients were classified as Steinbrocker stage III and 34/65 (52%) as Steinbrocker stage IV. Despite the low J-HAQ score (0.40) of our case series at the baseline, the number of patients in the different Steinbrocker classes were as follows: 1 in class 1, 35 in class 2, 27 in class 3, and 2 in class 4. The Steinbrocker Stage and Class in our study indicated that most patients had some irreversible ADL impairments. Furthermore, in the present study, the grip power was correlated with the J-HAQ score (ρ=-0.426, p<0.01) and DAS28-ESR (ρ=-0.417, p<0.01). Therefore, we consider it necessary to evaluate the grip power when assessing subclinical joint dysfunction. Consistent with our hypothesis, in the present study, treatment with GLM improved the grip power at 52 weeks and at the final follow-up. The use of GLM not only suppressed joint inflammation but also improved the grip power. Uutela et al. (35) reported that the grip power reflected the disease status, such as remission, low/moderate disease activity, and high disease activity. The present study showed that the grip power was correlated with the J-HAQ and DAS28-ESR as continuous variables. Eberhardt et al. reported that the use of TNF inhibitors for more than one year in patients with RA improved the grip power. However, details concerning the TNF inhibitors were not provided. As their study findings were published in 2007, GLM would not have been used (27). Aside from the abovementioned study by Eberhardt et al., there have been no reports showing improvements in the grip power following the use of TNF inhibitors. Our study is thus the first to show an improvement in the grip power in daily practice following GLM use. Improving the grip power may promote the prevention of sarcopenia and frailty in the future. Therefore, measuring the grip strength will likely provide supplemental information about potential ADL impairment. Only 17 patients (26.1%) discontinued the treatment course in our study, indicating a high continuation rate for long-term GLM use. The ANSWER cohort study, comprising 2,494 patients in real clinical practice, reported the retention rates of the following 7 bDMARDs: ABT (75.5%), TCZ (71.5%), GLM (65.6%), ETN (61.2%), certolizumab pegol (60.7%), ADA (58.2%), and IFX (53.4%) at 36 months in adjusted model (36). A systematic review by Svedbom et al. reported that the continuation rate of GLM was higher than that of other TNF inhibitors (9). An important characteristic of GLM is its lower antigenicity than other bDMARDs (37). The low antibody production against GLM is likely associated with its high continuity. Svedbom et al. showed that the respective continuation rates of GLM in real clinical practice at 52/104/156 weeks were 67-76%/49-63%/60% for bDMARD-naïve patients and 47-63%/40-61%/32-54% for bDMARD-switch patients (9). Kondo et al. reported that the continuation rate of GLM after 6 years was 50.3% (38). Compared with these data from real clinical practice, our study findings showed a better continuation rate of GLM in both the naïve and switch groups. However, the systematic review by Svedbom et al. included abstracts from academic conferences, which may have provided inadequate information. Therefore, it would be difficult to precisely analyze the reason for the difference between our findings and those of the systematic review. In our study, patients discontinued the treatment course due to a lack of efficacy (8/65: 12.3%), toxic effects (5/65: 7.7%), and other reasons (4/65: 6.2%). None of the patients discontinued the treatment due to remission. In the ANSWER cohort study, the drug retention rate of GLM in the adjusted model at 36 months was as follows: lack of effectiveness (74.0%), toxic effect (89.1%), and remission (92.5%) (28). Ten patients discontinued GLM within 26 weeks, and 3 discontinued between 26 and 52 weeks. Five patients discontinued GLM because of a lack of efficacy within 26 weeks. Kondo et al. reported that the discontinuation of the treatment course frequently occurred within six months (38). A steady-state plasma concentration can be achieved with 12 weeks of repeated injection of GLM (39), which is longer than that of other TNF-inhibitors (40). The GO-FORTH trial results showed that concurrent use of MTX leads to earlier disease control at three and six months than GLM monotherapy and switching therapy [based on the American College of Rheumatology criteria (41)] for two to five years (2,14,16). Considering the discontinuation of drug administration within 26 weeks in the present study, we suggest that tight control of the RA status within 26 weeks is necessary until GLM exhibits effectiveness, especially in monotherapy and switching therapy groups. The continuation rate was higher in patients who were administered MTX than in those who were not. Concurrent use of MTX with GLM decreases immunogenicity and adverse events (42). The patients without MTX were older and had higher CRP, ESR, MMP-3, and RF values than the patients with MTX; therefore, older patients and those with more severe inflammation are likely to be more adversely affected by continuation of GLM. According to the EULAR recommendation (17), if MTX is not contraindicated, it should be administered. It was challenging to administer MTX to patients without MTX because of other medical complications. Our data also showed a reduction in PSL use at the final follow-up, suggesting that the use of PSL for the short term soon after GLM induction would facilitate a decrease in disease activity until GLM exhibits effectiveness up to 26 weeks. Introduction of the 100-mg GLM regimen would facilitate the early suppression of disease and prevent early drop-out from treatment. Several limitations associated with the present study warrant mention. This was a retrospective study, and the sample size was smaller than that of clinical trials. Furthermore, the concurrent use of csDMARDs (including MTX and other csDMARDs) differed among the naïve and switch groups. The final selection and dosage of bDMARDs was decided by discussion between the patient and the doctor. The initial dose of GLM was decided while considering not only the patient's disease status but also their economic status. Our study lacks adequate data to explore the risk of discontinuation using a multivariate analysis, as 17 patients discontinued the study. Conclusion GLM improved the disease activity and grip power in bDMARD-naïve and switch groups. The concurrent use of MTX with GLM showed a better continuation rate than GLM administration without MTX. This is the first report to show the improvement in the grip power by GLM and to demonstrate that the use of GLM can prevent sarcopenia in the future. We also found that the grip power was correlated with the J-HAQ and DAS28-ESR. Our findings concerning the effects of GLM may facilitate further studies on effective RA treatment regimens. Author's disclosure of potential Conflicts of Interest (COI). Satoshi Ito: Honoraria, Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Jansen Pharma and Mitsubishi Tanabe. Hajime Ishikawa: Honoraria, Astellas, Chugai, Gilead Sciences and Corrona.	Subcutaneous	DrugAdministrationRoute	CC BY-NC-ND	33250460	18,599,924	2021-05-01
What was the dosage of drug 'METHOTREXATE'?	Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis. Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA. Introduction The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), such as golimumab (GLM), has transformed the treatment of rheumatoid arthritis (RA). GLM is a human monoclonal IgG antibody that binds to tumor necrosis factor-alpha (TNF-α) (1). GLM in combination with methotrexate (MTX) has shown efficacy and safety in phase III clinical trials (2-4). In Japan, the GO-FORTH (5) and GO-MONO (6) trials demonstrated the clinical efficacy and safety of GLM in combination with MTX and as monotherapy, respectively. Based on these data, the Japanese Pharmaceuticals and Medical Devices Agency approved GLM (50 and 100 mg) as the fourth anti-TNF-α antibody in 2011 (7); the 100 mg dose is only available in Japan (8). Sevedbom et al. performed a systematic review to determine the continuation rate of GLM (9). They identified 12 real-world studies; however, only 3 were original articles, whereas the remaining 9 were abstracts from academic conferences (10-12). There have been a few reports of the 100 mg GLM regimen in daily practice administered once every 4 weeks (8,11,13); these reports had follow-up periods of up to 52 weeks. Shono (13) compared the clinical safety and efficacy between a bio-naïve and bio-switch group and reported that the improvement in disease activity was similar between the groups at 24 weeks. Although the GO-FORWARD, GO-AFTER, GO-BEFORE, and GO-MONO studies were randomized controlled trials to show the efficacy and safety of GLM from 120 weeks to 5 years, they differed from studies in real clinical settings (2,14-16). The European League Against Rheumatism (EULAR) has recommended the short-term use of prednisolone (PSL) to control disease activity (17). Since a high dose of PSL has many adverse effects, reducing the dose is useful (18). MTX plays an important role in the treatment of RA, but it also has side effects (19), causing many patients to wish to taper or discontinue MTX therapy (20). Since the introduction of the treat-to-target strategy, patients have sought to achieve a high quality of life (QOL). The Japanese version of the health assessment questionnaire (J-HAQ) is an instrument for measuring the physical function and health-related QOL (21). Sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance” by the Asian Working Group for Sarcopenia in 2014, with a consensus update in 2019 (22). The diagnostic criterion of “low muscle strength” is defined as a grip power <28 kg for men and <18 kg for women. Sarcopenia enhances the fall burden, decreases healthy life expectancy, and increases healthcare costs (23,24). Previous reports on the prevalence of sarcopenia have varied; for example, a meta-analysis showed that the prevalence of sarcopenia in patients with RA was 15-32% (25), and Torii et al. reported a prevalence of 37.1% in Japanese patients (23). In addition, Ishikawa et al. reported that the handgrip power in Japanese patients with RA reflects the level of independence in activity of daily living (ADL), and the cut-off value for independent ADL was 136.5 mmHg (11.8 kgw) for women and 152.5 mmHg (13.5 kgw) for men (26). Only one report has described an improvement in the grip power following the use of bDMARDs, with the use of TNF inhibitors for more than one year being shown to improve the grip power in patients with RA (27). We hypothesized that improving the grip power can not only ameliorate inflammation in the upper extremities in patients with RA but also decrease sarcopenia and increase the healthy life expectancy. We hypothesized that the long-term use of GLM would be safe and effective in bio-naïve and bio-switch patients in real clinical practice and that the use of GLM would facilitate better disease control, reduce the PSL and MTX dosages, and improve the J-HAQ and grip power. Furthermore, we hypothesized that the grip power correlates with the J-HAQ score and Disease Activity Score (DAS) 28-ESR. Therefore, in the present study, we evaluated the effectiveness and drug continuation rate of long-term use of GLM in bDMARD-naïve and switch patients in clinical practice in order to determine the reason for discontinuation because of a lack of efficacy. Materials and Methods We retrospectively analyzed the data of patients with RA administered GLM at Niigata Rheumatic Center from October 2011 to March 2015. Sixty-five patients (58 women and 7 men) started GLM therapy during this period. All patients were followed up for more than 52 weeks. Data were collected in March 2016 and retrospectively analyzed (Table 1). The patients were divided into bDMARD “naïve” and “switch” groups based on their history of use. Table 1. Characteristics of Patients in the Naïve and Switch Groups. Total (n=65) Naïve (n=28) Switch (n=37) p value Female, n (%) 58 (89%) 25 (89%) 33 (89%) 0.990 Age, years 69 (61-74) 68 (60-71) 70 (60-76) 0.180 Disease duration of RA, years 9 (5-16) 10 (2-20) 9 (7-16) 0.418 Follow up period 134 (58-162) 127 (79-148) 142 (80-170) 0.310 Swollen joint count 3 (1-6) 3 (1-6) 2 (0-6) 0.414 Tender joint count 3 (1-6) 4 (1-8) 2 (1-5) 0.149 Patient’s global VAS score, mm 46 (23-59) 47 (25-60) 46 (21-59) 0.842 Doctor’s global VAS score, mm 35 (23-60) 40 (26-60) 35 (19-52) 0.524 ESR, mm/h 23 (12-50) 24 (10-49) 23 (14-50) 0.628 CRP, mg/dL 0.60 (0.10-2.10) 0.40 (0.1-1.8) 0.80 (0.10-2.55) 0.110 RF, IU/mL 47 (18-112) 73 (21-231) 43 (11-99) 0.040* RF, positive (%) 49 (75%) 26 (93%) 23 (62%) 0.003* ACPA, U/mL 88 (22-244) 117 (22-248) 67 (25-213) 0.367 ACPA, positive (%) 57 (87%) 26 (93%) 31 (84%) 0.172 MMP-3, ng/mL 128 (67-214) 93 (62-171) 142 (70-249) 0.161 DAS28-ESR 4.27 (3.35-5.19) 4.31 (3.52-5.25) 4.27 (3.19-4.89) 0.521 J-HAQ 0.40 (0.05-0.84) 0.25 (0.04-0.71) 0.48(0.21-0.88) 0.223 MTX use, n (%) 43 (66%) 22 (79%) 21 (57%) 0.066 Dose of MTX, mg/week 8.0 (0.0-10.0) 8.0 (6.0-10.0) 5.0 (0.0-8.5) 0.046* PSL use, n (%) 42(65%) 16 (57%) 26 (70%) 0.299 Dose of PSL, mg/day 3.0 (0.0-5.0) 2.3 (0.0-5.0) 3.0 (0.0-5.0) 0.299 Steinbrocker Stage (I, II, III, IV) 4:10:17:34 3:5:6:14 1:5:11:20 0.507 Steinbrocker Class (1, 2, 3, 4) 1:35:27:2 1:20:7:0 0:15:20:2 0.030* Initial dose of GLM (50 mg:100 mg) 38:27 24:4 14:23 <0.001** Number of patients with dose escalation, n (%) 20 (31%) 13 (46%) 7 (19%) 0.017* Number of patients who discontinued treatment, n (%) 17 (26%) 6 (21%) 11 (30%) 0.450 P value was calculated by comparing naïve and switch groups. A chi-square test was used for comparison of categorical data between the two groups. The Mann-Whitney U test was used to assess continuous variables of non-paired data. : p<0.05, : p<0.01. Median (range). RA: rheumatoid arthritis, VAS: visual analog scale, ESR: erythrocyte sedimentation rate, CRP: the serum C-reactive protein, RF: rheumatoid factor (positive ≥15), ACPA: anti-cyclic citrullinated peptide antibody (positive ≥4.5), MMP-3: matrix metalloprotease, DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone, Steinbrocker Stage: Classification of the structural state of rheumatoid arthritis (I, II, III, IV), Steinbrocker Class: Classification of the functional state of rheumatoid arthritis (1, 2, 3, 4), GLM: golimumab Informed consent was obtained in the form of an opt-out on a poster. No patients were excluded. Signed informed consent was not required by the ethics committee because this was a retrospective study. This study was performed according to Declaration of Helsinki and was approved by the Niigata Rheumatic Center ethics committee. The diagnosis of RA was based on the 2010 American College of Rheumatology/EULAR classification criteria (28). Patients who had previously used GLM or had congestive heart failure, active tuberculosis, or active infectious diseases were excluded. The GLM induction and dose were decided by discussion between the treating doctor and the patient based on the EULAR recommendations for the management of RA (17). Although 50 mg of GLM is recommended to be used with MTX in Japan (20), we used 50 mg of GLM without MTX for 2 patients in the naïve group and 6 patients in the switch group. GLM was injected subcutaneously every four weeks at the hospital by the medical staff. We evaluated the age, sex, follow-up period, and history of bDMARDs use, MTX use, and corticosteroid use as patients' baseline characteristics. The RA status was evaluated at 0 and 52 weeks and at the final follow-up based on the following: DAS28-ESR, MTX dose, and PSL dose. The grip power and J-HAQ were also assessed to determine the improvement in the ADL (26). The average grip power of both hands was measured using a mercury dynamometer, which was able to measure from 0 to 300 mmHg (28.9 kg). The patients were divided into bDMARD naïve and switch groups and compared with each other. The continuation rate of GLM was compared between the groups. In addition, we compared the continuation rate of GLM in patients who had and had not been administered MTX. The demographic parameters of patients who did and did not use MTX were also compared. Statistical analyses Statistical analyses were performed using the JMPⓇ 14 software program (SAS Institute, Cary, USA). The chi-square test was used for comparisons between two groups for categorical data, while Wilcoxon's signed rank test was used for continuous variables of paired data. In the comparison of continuous variables (baseline vs. 52 weeks and at final follow-up), 13 patients who discontinued GLM treatment before 52 weeks were excluded. The continuous variables at 52 weeks and at the final follow-up were compared with those at baseline by Wilcoxon's signed rank test adjusted using the Holm method. Regarding the Holm method, first, the p values at 52 weeks and at the final follow-up were compared. If the lower of these p values was <0.025 (0.05/2), the difference was considered significant. If the lower of these p values was ≥0.025, then both p values were considered not significant. If the higher of these p value was <0.05, the difference was considered significant. A one-sided Wilcoxon's signed rank test was performed to evaluate the reduction in the DAS28-ESR, J-HAQ, MTX dose, and PSL dose. In addition, Wilcoxon's signed rank test was performed to evaluate the improvement in the grip power. Spearman correlation analysis was performed to determine the correlation of grip power value, J-HAQ, and DAS28-ESR at the baseline, 52 weeks, and the final follow-up. The Mann-Whitney U test was used to assess continuous variables of non-paired data. To compare the drug continuation rate between both groups, a log-rank test with the Kaplan-Meier method was used. The last observation carried forward (LOCF) method was used for missing data (29). Results Patients' characteristics Sixty-five patients (58 women and 7 men) were included in the present study (Table 1). The median (range) age of patients was 69 (61-74) years old, and the median disease duration was 9 (5-16) years. Among the 65 patients, 28 were biologic-naïve (naïve group), and 37 had switched from biologics (switch group). The median (range) follow-up period was 134 (58-162) weeks. MTX was administered in 66% (43/65) of patients at a median (range) dose of 8.0 (0.0-10.0) mg/week. PSL was administered to 65% (42/65) of patients at a median (range) dose of 3.0 (0.0-5.0) mg/day. Other conventional DMARDs (csDMARDs) were used as follows: salazosulfapyridine in 23 cases (naïve/switch=14/9), mizoribine in 19 cases (5/14), bucillamine in 9 cases (3/6), tacrolimus hydrate in 5 cases (1/4), iguratimod in 4 cases (2/2), and actarit in 4 cases (1/3). In the switch group, 31 patients received GLM as the second bDMARD, 5 patients received it as the third bDMARD, and 1 received it as the fifth bDMARD. Moreover, patients in the switch group received infliximab (IFX) (as the first and second bDMARDs: 18, 1 case), etanercept (ETN) (as the first and second bDMARDs: 13, 3 cases), tocilizumab (TCZ) (as the first and third bDMARD: 4, 1 case), abatacept (ABT) (as the first and fourth bDMARD: 1, 1 case), and adalimumab (ADA) (as first and second bDMARD: 1, 2 cases). There was no significant difference in the baseline status between the naïve and switch groups except for with regard to the rheumatoid factor, MTX dose, Steinbrocker Class, and initial dose of GLM (Table 1) (30). Twenty-four patients in the naïve group received 50 mg GLM; the dose was increased to 100 mg in 13 patients. Fourteen patients in the switch group received 50 mg GLM; the dose was increased to 100 mg in 7 patients. The proportion of patients who were administered 100 mg GLM as the initial dose was higher in the switch group (23/37; 62%) than in the naïve group (4/28; 14%; p<0.001). Efficacy results The median (range) DAS28-ESR value was 4.31 (3.52-5.25) in the naïve group and 4.27 (3.19-4.89) in the switch group at baseline (Table 2). At the final follow-up, the median (range) DAS28-ESR value had improved to 2.65 (2.28-3.77) in the naïve group and 2.89 (2.49-3.88) in the switch group. The J-HAQ did not improve in either group. The ratio of low disease activity and remission improved from naïve 18% (5/28)/switch 24% (9/37) at baseline to naïve 60% (15/25)/switch 52% (14/27) at 52 weeks (p<0.05) and naïve 64% (16/25)/switch 67% (18/27) at the final follow-up (p<0.01) (Fig. 1). The median grip power at 52 weeks and at the final follow-up improved in both groups. The MTX and PSL doses were decreased at the final follow-up. The Spearman correlation coefficients of the grip power, J-HAQ, and DAS28-ESR were ρ=-0.426 (grip power vs. J-HAQ), ρ=-0.417 (grip power vs. DAS28-ESR), and ρ=0.348 (J-HAQ vs. DAS28-ESR) (p<0.001). Table 2. The Clinical Course of Golimumab. Week 0 Week 52 Final follow-up Median (range) Median (range) p value Median (range) p value DAS28-ESR Naïve 4.31 (3.52-5.25) 2.76 (2.23-4.05) <0.001 2.65 (2.28-3.77) <0.001* Switch 4.27 (3.19-4.89) 2.69 (2.19-3.78) 0.001* 2.89 (2.49-3.88) 0.006* Total 4.27 (3.35-4.27) 2.73 (2.22-3.90) <0.001* 2.73 (2.35-3.77) <0.001* J-HAQ Naïve 0.25 (0.04-0.71) 0.25 (0.05-1.03) 0.593 0.23 (0.04-0.80) 0.771 Switch 0.48 (0.25-0.85) 0.53 (0.23-0.88) 0.490 0.53 (0.10-0.85) 0.608 Total 0.40 (0.05-0.84) 0.40 (0.07-0.93) 0.552 0.30 (0.10-0.84) 0.761 Grip power, mmHg Naïve 138 (104-183) 160 (102-231) <0.001* 183 (100-234) 0.041* Switch 127 (93-168) 158 (112-195) 0.026* 154 (115-190) <0.001* Total 133 (96-179) 158 (107-204) <0.001* 165(105-208) <0.001* Dose of MTX, mg/week Naïve 8.0 (6.0-10.0) 8.0 (3.0-8.5) 0.006* 5.0 (0.0-8.0) <0.001* Switch 5.0 (0.0-8.5) 6.0 (0.0-9.0) 0.091 6.0 (0.0-8.0) 0.007* Total 8.0 (0.0-10.0) 7.0 (1.3-8.8) 0.003* 5.5 (0.0-8.0) <0.001* Dose of PSL, mg/day Naïve 2.3 (0.0-5.0) 2.0 (0.0-5.0) 0.110 2.0 (0.0-3.8) 0.016* Switch 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.040 2.5 (0.0-4.0) 0.004* Total 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.016* 2.3 (0.0-4.0) <0.001* At 52 weeks and at the final follow-up, each parameter was compared with the baseline value using the Wilcoxon rank sum test adjusted by the Holm method. *: significant difference. Median (range). DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone Figure 1. The DAS28-ESR at baseline, 52 weeks, and the final follow-up. The DAS28-ESR classification improved from baseline to 52 weeks and at the final follow-up in both groups (chi-square test: p<0.05). The classification of DAS28-ESR was as follows: remission, DAS28-ESR<2.6; low disease activity, 2.6≤DAS28-ESR<3.2; moderate disease activity, 3.2≤DAS28-ESR≤5.1; high disease activity, DAS28-ESR>5.1. DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate Continuation rate and reason for discontinuation The continuation rate at the final follow-up [median (range): 134 (58-162) weeks] was 22/28 (78.6%) in the naïve group and 26/37 (70.3%) in the switch group. The respective continuation rates of the naïve/switch/total groups calculated using the Kaplan-Meier method were 89.3%/73.0%/80.0% at 52 weeks, 81.1%/73.0%/76.4% at 104 weeks, and 76.3%/68.7%/71.6% at 156 weeks (Fig. 2). No significant difference was detected in the continuation rate between the naïve and switch groups (p=0.829). The continuation rate in patients who were administered MTX was higher than that in patients who were not administered MTX (p=0.001; Fig. 3). On comparing the backgrounds of the naïve and switch groups, patients without MTX had higher median (range) values for the age, C-reactive protein (CRP), ESR, matrix metalloprotease-3 (MMP-3), and rheumatoid factor (RF) at baseline than those with MTX (p<0.05) [patients without MTX vs. patients with MTX, age 73 (69-78) vs. 65 (54-70), CRP 1.65 (0.25-3.23) vs. 0.40 (0.10-1.50), ESR 45 (23-80) vs. 18 (10-28), MMP-3 171 (87-367) vs. 95 (60-194), RF 83 (33-162) vs. 23 (13-106)]. Seventeen patients discontinued the administration of GLM. The reasons for discontinuation were as follows: lack of efficacy (8/65: 12.3%), infection (3/65: 4.6%), and eczema, multiple sclerosis, economic reasons, patient preference for bDMARDs, fracture, and transfer to another hospital in 1 case each (1/65: 1.5%). Ten patients (1 naïve, 9 switch) discontinued GLM within 26 weeks, and 3 discontinued GLM between 26 and 52 weeks. Five patients discontinued GLM within 26 weeks because of a lack of efficacy. No patients discontinued GLM due to remission. Figure 2. Drug continuation rates in the naïve and switch groups. The drug continuation rate showed no significant difference between both groups (log rank: p=0.829). Figure 3. Drug continuation rates in groups administered GLM with and without MTX. The group administered GLM with MTX showed a better drug continuation rate than the group administered GLM without MTX (log rank: p=0.004). GLM: golimumab, MTX: methotrexate Discussion In this study, evaluated the effectiveness and continuation rate of GLM for long-term use in daily practice for patients with RA. We recorded the clinical effect and the continuation rate of GLM in daily practice after 52 weeks. As hypothesized, GLM showed effectiveness not only in bDMARD-naïve patients but also in switch patients. In our institution, 38 patients started GLM 50 mg; however, 20 increased the dose to 100 mg because the 50-mg regimen was inadequate. Increasing the dose improved the DAS; therefore, if the 50-mg regimen is not effective, increasing the dose should be considered. The GO-AFTER study has also reported the clinical efficacy of switching to GLM therapy (14). In agreement with this finding, we found that GLM therapy was effective even for the switch group patients. The remission rate of the naïve/switch group was 40% (10/25)/41% (11/27) at 52 weeks and 44% (11/25)/33% (9/27) at the final follow-up. In the GO-FORTH and GO-FORWARD trials, the rates of remission based on the DAS28-ESR were 32.4-52.2% at 52 weeks, 39.4-75.8% at 104 weeks, and 55.3-61.8% at 156 weeks (2,5). In 2 previous studies, the average age at the baseline was 50 years old, and the average DAS28-ESR at the baseline was 5.5-5.9; these patients showed better remission rates at 52 and 104 weeks than did our patients (2,5). In our trial, the median age of the recruited patients was 69 years old. Thus, the age and age-related complications might have affected the remission rate in our patients. In the GO-AFTER trial, the remission rate of the bDMARD switch group for 52/100/160 weeks was 12.5-15.6% for the 50 mg regimen and 21.5-22.1% for the 100 mg regimen (3). The switch group in our study showed a better remission rate than that in the GO-AFTER study. The higher the remission rate of the switch group in our study may have been due to the better DAS28-ESR at baseline than in the GO-AFTER study. In the present study, we recruited older patients than those described in previous studies (16,31,32), and we therefore believe that the 65 patients that were collected from a single institution with 134 (58-162) weeks of follow-up thus provided valuable information in comparison to previous studies. The J-HAQ was not improved at the final follow-up compared with that at the baseline in the present study, which was inconsistent with our hypothesis. The HAQ score in healthy populations was reported to be 0.49 (33). The GO-FORWARD, GO-FORTH, GO-AFTER, and GO-MONO trials reported improvements in the HAQ-DI (0.37-0.75), and the HAQ-DI baseline values ranged from 0.9 to 1.6 (6,31,32,34). In these 4 clinical trials, the mean age ranged from 50-55 years old, and the mean DAS28-ESR ranged from 5.5-6.3. The age and DAS28-ESR were higher in our study than in those previous trials. Furthermore, in our study, 17/65 (26%) patients were classified as Steinbrocker stage III and 34/65 (52%) as Steinbrocker stage IV. Despite the low J-HAQ score (0.40) of our case series at the baseline, the number of patients in the different Steinbrocker classes were as follows: 1 in class 1, 35 in class 2, 27 in class 3, and 2 in class 4. The Steinbrocker Stage and Class in our study indicated that most patients had some irreversible ADL impairments. Furthermore, in the present study, the grip power was correlated with the J-HAQ score (ρ=-0.426, p<0.01) and DAS28-ESR (ρ=-0.417, p<0.01). Therefore, we consider it necessary to evaluate the grip power when assessing subclinical joint dysfunction. Consistent with our hypothesis, in the present study, treatment with GLM improved the grip power at 52 weeks and at the final follow-up. The use of GLM not only suppressed joint inflammation but also improved the grip power. Uutela et al. (35) reported that the grip power reflected the disease status, such as remission, low/moderate disease activity, and high disease activity. The present study showed that the grip power was correlated with the J-HAQ and DAS28-ESR as continuous variables. Eberhardt et al. reported that the use of TNF inhibitors for more than one year in patients with RA improved the grip power. However, details concerning the TNF inhibitors were not provided. As their study findings were published in 2007, GLM would not have been used (27). Aside from the abovementioned study by Eberhardt et al., there have been no reports showing improvements in the grip power following the use of TNF inhibitors. Our study is thus the first to show an improvement in the grip power in daily practice following GLM use. Improving the grip power may promote the prevention of sarcopenia and frailty in the future. Therefore, measuring the grip strength will likely provide supplemental information about potential ADL impairment. Only 17 patients (26.1%) discontinued the treatment course in our study, indicating a high continuation rate for long-term GLM use. The ANSWER cohort study, comprising 2,494 patients in real clinical practice, reported the retention rates of the following 7 bDMARDs: ABT (75.5%), TCZ (71.5%), GLM (65.6%), ETN (61.2%), certolizumab pegol (60.7%), ADA (58.2%), and IFX (53.4%) at 36 months in adjusted model (36). A systematic review by Svedbom et al. reported that the continuation rate of GLM was higher than that of other TNF inhibitors (9). An important characteristic of GLM is its lower antigenicity than other bDMARDs (37). The low antibody production against GLM is likely associated with its high continuity. Svedbom et al. showed that the respective continuation rates of GLM in real clinical practice at 52/104/156 weeks were 67-76%/49-63%/60% for bDMARD-naïve patients and 47-63%/40-61%/32-54% for bDMARD-switch patients (9). Kondo et al. reported that the continuation rate of GLM after 6 years was 50.3% (38). Compared with these data from real clinical practice, our study findings showed a better continuation rate of GLM in both the naïve and switch groups. However, the systematic review by Svedbom et al. included abstracts from academic conferences, which may have provided inadequate information. Therefore, it would be difficult to precisely analyze the reason for the difference between our findings and those of the systematic review. In our study, patients discontinued the treatment course due to a lack of efficacy (8/65: 12.3%), toxic effects (5/65: 7.7%), and other reasons (4/65: 6.2%). None of the patients discontinued the treatment due to remission. In the ANSWER cohort study, the drug retention rate of GLM in the adjusted model at 36 months was as follows: lack of effectiveness (74.0%), toxic effect (89.1%), and remission (92.5%) (28). Ten patients discontinued GLM within 26 weeks, and 3 discontinued between 26 and 52 weeks. Five patients discontinued GLM because of a lack of efficacy within 26 weeks. Kondo et al. reported that the discontinuation of the treatment course frequently occurred within six months (38). A steady-state plasma concentration can be achieved with 12 weeks of repeated injection of GLM (39), which is longer than that of other TNF-inhibitors (40). The GO-FORTH trial results showed that concurrent use of MTX leads to earlier disease control at three and six months than GLM monotherapy and switching therapy [based on the American College of Rheumatology criteria (41)] for two to five years (2,14,16). Considering the discontinuation of drug administration within 26 weeks in the present study, we suggest that tight control of the RA status within 26 weeks is necessary until GLM exhibits effectiveness, especially in monotherapy and switching therapy groups. The continuation rate was higher in patients who were administered MTX than in those who were not. Concurrent use of MTX with GLM decreases immunogenicity and adverse events (42). The patients without MTX were older and had higher CRP, ESR, MMP-3, and RF values than the patients with MTX; therefore, older patients and those with more severe inflammation are likely to be more adversely affected by continuation of GLM. According to the EULAR recommendation (17), if MTX is not contraindicated, it should be administered. It was challenging to administer MTX to patients without MTX because of other medical complications. Our data also showed a reduction in PSL use at the final follow-up, suggesting that the use of PSL for the short term soon after GLM induction would facilitate a decrease in disease activity until GLM exhibits effectiveness up to 26 weeks. Introduction of the 100-mg GLM regimen would facilitate the early suppression of disease and prevent early drop-out from treatment. Several limitations associated with the present study warrant mention. This was a retrospective study, and the sample size was smaller than that of clinical trials. Furthermore, the concurrent use of csDMARDs (including MTX and other csDMARDs) differed among the naïve and switch groups. The final selection and dosage of bDMARDs was decided by discussion between the patient and the doctor. The initial dose of GLM was decided while considering not only the patient's disease status but also their economic status. Our study lacks adequate data to explore the risk of discontinuation using a multivariate analysis, as 17 patients discontinued the study. Conclusion GLM improved the disease activity and grip power in bDMARD-naïve and switch groups. The concurrent use of MTX with GLM showed a better continuation rate than GLM administration without MTX. This is the first report to show the improvement in the grip power by GLM and to demonstrate that the use of GLM can prevent sarcopenia in the future. We also found that the grip power was correlated with the J-HAQ and DAS28-ESR. Our findings concerning the effects of GLM may facilitate further studies on effective RA treatment regimens. Author's disclosure of potential Conflicts of Interest (COI). Satoshi Ito: Honoraria, Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Jansen Pharma and Mitsubishi Tanabe. Hajime Ishikawa: Honoraria, Astellas, Chugai, Gilead Sciences and Corrona.	8 mg (milligrams).	DrugDosage	CC BY-NC-ND	33250460	18,599,924	2021-05-01
What was the dosage of drug 'PREDNISOLONE'?	Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis. Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA. Introduction The emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), such as golimumab (GLM), has transformed the treatment of rheumatoid arthritis (RA). GLM is a human monoclonal IgG antibody that binds to tumor necrosis factor-alpha (TNF-α) (1). GLM in combination with methotrexate (MTX) has shown efficacy and safety in phase III clinical trials (2-4). In Japan, the GO-FORTH (5) and GO-MONO (6) trials demonstrated the clinical efficacy and safety of GLM in combination with MTX and as monotherapy, respectively. Based on these data, the Japanese Pharmaceuticals and Medical Devices Agency approved GLM (50 and 100 mg) as the fourth anti-TNF-α antibody in 2011 (7); the 100 mg dose is only available in Japan (8). Sevedbom et al. performed a systematic review to determine the continuation rate of GLM (9). They identified 12 real-world studies; however, only 3 were original articles, whereas the remaining 9 were abstracts from academic conferences (10-12). There have been a few reports of the 100 mg GLM regimen in daily practice administered once every 4 weeks (8,11,13); these reports had follow-up periods of up to 52 weeks. Shono (13) compared the clinical safety and efficacy between a bio-naïve and bio-switch group and reported that the improvement in disease activity was similar between the groups at 24 weeks. Although the GO-FORWARD, GO-AFTER, GO-BEFORE, and GO-MONO studies were randomized controlled trials to show the efficacy and safety of GLM from 120 weeks to 5 years, they differed from studies in real clinical settings (2,14-16). The European League Against Rheumatism (EULAR) has recommended the short-term use of prednisolone (PSL) to control disease activity (17). Since a high dose of PSL has many adverse effects, reducing the dose is useful (18). MTX plays an important role in the treatment of RA, but it also has side effects (19), causing many patients to wish to taper or discontinue MTX therapy (20). Since the introduction of the treat-to-target strategy, patients have sought to achieve a high quality of life (QOL). The Japanese version of the health assessment questionnaire (J-HAQ) is an instrument for measuring the physical function and health-related QOL (21). Sarcopenia was defined as “age-related loss of muscle mass, plus low muscle strength, and/or low physical performance” by the Asian Working Group for Sarcopenia in 2014, with a consensus update in 2019 (22). The diagnostic criterion of “low muscle strength” is defined as a grip power <28 kg for men and <18 kg for women. Sarcopenia enhances the fall burden, decreases healthy life expectancy, and increases healthcare costs (23,24). Previous reports on the prevalence of sarcopenia have varied; for example, a meta-analysis showed that the prevalence of sarcopenia in patients with RA was 15-32% (25), and Torii et al. reported a prevalence of 37.1% in Japanese patients (23). In addition, Ishikawa et al. reported that the handgrip power in Japanese patients with RA reflects the level of independence in activity of daily living (ADL), and the cut-off value for independent ADL was 136.5 mmHg (11.8 kgw) for women and 152.5 mmHg (13.5 kgw) for men (26). Only one report has described an improvement in the grip power following the use of bDMARDs, with the use of TNF inhibitors for more than one year being shown to improve the grip power in patients with RA (27). We hypothesized that improving the grip power can not only ameliorate inflammation in the upper extremities in patients with RA but also decrease sarcopenia and increase the healthy life expectancy. We hypothesized that the long-term use of GLM would be safe and effective in bio-naïve and bio-switch patients in real clinical practice and that the use of GLM would facilitate better disease control, reduce the PSL and MTX dosages, and improve the J-HAQ and grip power. Furthermore, we hypothesized that the grip power correlates with the J-HAQ score and Disease Activity Score (DAS) 28-ESR. Therefore, in the present study, we evaluated the effectiveness and drug continuation rate of long-term use of GLM in bDMARD-naïve and switch patients in clinical practice in order to determine the reason for discontinuation because of a lack of efficacy. Materials and Methods We retrospectively analyzed the data of patients with RA administered GLM at Niigata Rheumatic Center from October 2011 to March 2015. Sixty-five patients (58 women and 7 men) started GLM therapy during this period. All patients were followed up for more than 52 weeks. Data were collected in March 2016 and retrospectively analyzed (Table 1). The patients were divided into bDMARD “naïve” and “switch” groups based on their history of use. Table 1. Characteristics of Patients in the Naïve and Switch Groups. Total (n=65) Naïve (n=28) Switch (n=37) p value Female, n (%) 58 (89%) 25 (89%) 33 (89%) 0.990 Age, years 69 (61-74) 68 (60-71) 70 (60-76) 0.180 Disease duration of RA, years 9 (5-16) 10 (2-20) 9 (7-16) 0.418 Follow up period 134 (58-162) 127 (79-148) 142 (80-170) 0.310 Swollen joint count 3 (1-6) 3 (1-6) 2 (0-6) 0.414 Tender joint count 3 (1-6) 4 (1-8) 2 (1-5) 0.149 Patient’s global VAS score, mm 46 (23-59) 47 (25-60) 46 (21-59) 0.842 Doctor’s global VAS score, mm 35 (23-60) 40 (26-60) 35 (19-52) 0.524 ESR, mm/h 23 (12-50) 24 (10-49) 23 (14-50) 0.628 CRP, mg/dL 0.60 (0.10-2.10) 0.40 (0.1-1.8) 0.80 (0.10-2.55) 0.110 RF, IU/mL 47 (18-112) 73 (21-231) 43 (11-99) 0.040* RF, positive (%) 49 (75%) 26 (93%) 23 (62%) 0.003* ACPA, U/mL 88 (22-244) 117 (22-248) 67 (25-213) 0.367 ACPA, positive (%) 57 (87%) 26 (93%) 31 (84%) 0.172 MMP-3, ng/mL 128 (67-214) 93 (62-171) 142 (70-249) 0.161 DAS28-ESR 4.27 (3.35-5.19) 4.31 (3.52-5.25) 4.27 (3.19-4.89) 0.521 J-HAQ 0.40 (0.05-0.84) 0.25 (0.04-0.71) 0.48(0.21-0.88) 0.223 MTX use, n (%) 43 (66%) 22 (79%) 21 (57%) 0.066 Dose of MTX, mg/week 8.0 (0.0-10.0) 8.0 (6.0-10.0) 5.0 (0.0-8.5) 0.046* PSL use, n (%) 42(65%) 16 (57%) 26 (70%) 0.299 Dose of PSL, mg/day 3.0 (0.0-5.0) 2.3 (0.0-5.0) 3.0 (0.0-5.0) 0.299 Steinbrocker Stage (I, II, III, IV) 4:10:17:34 3:5:6:14 1:5:11:20 0.507 Steinbrocker Class (1, 2, 3, 4) 1:35:27:2 1:20:7:0 0:15:20:2 0.030* Initial dose of GLM (50 mg:100 mg) 38:27 24:4 14:23 <0.001** Number of patients with dose escalation, n (%) 20 (31%) 13 (46%) 7 (19%) 0.017* Number of patients who discontinued treatment, n (%) 17 (26%) 6 (21%) 11 (30%) 0.450 P value was calculated by comparing naïve and switch groups. A chi-square test was used for comparison of categorical data between the two groups. The Mann-Whitney U test was used to assess continuous variables of non-paired data. : p<0.05, : p<0.01. Median (range). RA: rheumatoid arthritis, VAS: visual analog scale, ESR: erythrocyte sedimentation rate, CRP: the serum C-reactive protein, RF: rheumatoid factor (positive ≥15), ACPA: anti-cyclic citrullinated peptide antibody (positive ≥4.5), MMP-3: matrix metalloprotease, DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone, Steinbrocker Stage: Classification of the structural state of rheumatoid arthritis (I, II, III, IV), Steinbrocker Class: Classification of the functional state of rheumatoid arthritis (1, 2, 3, 4), GLM: golimumab Informed consent was obtained in the form of an opt-out on a poster. No patients were excluded. Signed informed consent was not required by the ethics committee because this was a retrospective study. This study was performed according to Declaration of Helsinki and was approved by the Niigata Rheumatic Center ethics committee. The diagnosis of RA was based on the 2010 American College of Rheumatology/EULAR classification criteria (28). Patients who had previously used GLM or had congestive heart failure, active tuberculosis, or active infectious diseases were excluded. The GLM induction and dose were decided by discussion between the treating doctor and the patient based on the EULAR recommendations for the management of RA (17). Although 50 mg of GLM is recommended to be used with MTX in Japan (20), we used 50 mg of GLM without MTX for 2 patients in the naïve group and 6 patients in the switch group. GLM was injected subcutaneously every four weeks at the hospital by the medical staff. We evaluated the age, sex, follow-up period, and history of bDMARDs use, MTX use, and corticosteroid use as patients' baseline characteristics. The RA status was evaluated at 0 and 52 weeks and at the final follow-up based on the following: DAS28-ESR, MTX dose, and PSL dose. The grip power and J-HAQ were also assessed to determine the improvement in the ADL (26). The average grip power of both hands was measured using a mercury dynamometer, which was able to measure from 0 to 300 mmHg (28.9 kg). The patients were divided into bDMARD naïve and switch groups and compared with each other. The continuation rate of GLM was compared between the groups. In addition, we compared the continuation rate of GLM in patients who had and had not been administered MTX. The demographic parameters of patients who did and did not use MTX were also compared. Statistical analyses Statistical analyses were performed using the JMPⓇ 14 software program (SAS Institute, Cary, USA). The chi-square test was used for comparisons between two groups for categorical data, while Wilcoxon's signed rank test was used for continuous variables of paired data. In the comparison of continuous variables (baseline vs. 52 weeks and at final follow-up), 13 patients who discontinued GLM treatment before 52 weeks were excluded. The continuous variables at 52 weeks and at the final follow-up were compared with those at baseline by Wilcoxon's signed rank test adjusted using the Holm method. Regarding the Holm method, first, the p values at 52 weeks and at the final follow-up were compared. If the lower of these p values was <0.025 (0.05/2), the difference was considered significant. If the lower of these p values was ≥0.025, then both p values were considered not significant. If the higher of these p value was <0.05, the difference was considered significant. A one-sided Wilcoxon's signed rank test was performed to evaluate the reduction in the DAS28-ESR, J-HAQ, MTX dose, and PSL dose. In addition, Wilcoxon's signed rank test was performed to evaluate the improvement in the grip power. Spearman correlation analysis was performed to determine the correlation of grip power value, J-HAQ, and DAS28-ESR at the baseline, 52 weeks, and the final follow-up. The Mann-Whitney U test was used to assess continuous variables of non-paired data. To compare the drug continuation rate between both groups, a log-rank test with the Kaplan-Meier method was used. The last observation carried forward (LOCF) method was used for missing data (29). Results Patients' characteristics Sixty-five patients (58 women and 7 men) were included in the present study (Table 1). The median (range) age of patients was 69 (61-74) years old, and the median disease duration was 9 (5-16) years. Among the 65 patients, 28 were biologic-naïve (naïve group), and 37 had switched from biologics (switch group). The median (range) follow-up period was 134 (58-162) weeks. MTX was administered in 66% (43/65) of patients at a median (range) dose of 8.0 (0.0-10.0) mg/week. PSL was administered to 65% (42/65) of patients at a median (range) dose of 3.0 (0.0-5.0) mg/day. Other conventional DMARDs (csDMARDs) were used as follows: salazosulfapyridine in 23 cases (naïve/switch=14/9), mizoribine in 19 cases (5/14), bucillamine in 9 cases (3/6), tacrolimus hydrate in 5 cases (1/4), iguratimod in 4 cases (2/2), and actarit in 4 cases (1/3). In the switch group, 31 patients received GLM as the second bDMARD, 5 patients received it as the third bDMARD, and 1 received it as the fifth bDMARD. Moreover, patients in the switch group received infliximab (IFX) (as the first and second bDMARDs: 18, 1 case), etanercept (ETN) (as the first and second bDMARDs: 13, 3 cases), tocilizumab (TCZ) (as the first and third bDMARD: 4, 1 case), abatacept (ABT) (as the first and fourth bDMARD: 1, 1 case), and adalimumab (ADA) (as first and second bDMARD: 1, 2 cases). There was no significant difference in the baseline status between the naïve and switch groups except for with regard to the rheumatoid factor, MTX dose, Steinbrocker Class, and initial dose of GLM (Table 1) (30). Twenty-four patients in the naïve group received 50 mg GLM; the dose was increased to 100 mg in 13 patients. Fourteen patients in the switch group received 50 mg GLM; the dose was increased to 100 mg in 7 patients. The proportion of patients who were administered 100 mg GLM as the initial dose was higher in the switch group (23/37; 62%) than in the naïve group (4/28; 14%; p<0.001). Efficacy results The median (range) DAS28-ESR value was 4.31 (3.52-5.25) in the naïve group and 4.27 (3.19-4.89) in the switch group at baseline (Table 2). At the final follow-up, the median (range) DAS28-ESR value had improved to 2.65 (2.28-3.77) in the naïve group and 2.89 (2.49-3.88) in the switch group. The J-HAQ did not improve in either group. The ratio of low disease activity and remission improved from naïve 18% (5/28)/switch 24% (9/37) at baseline to naïve 60% (15/25)/switch 52% (14/27) at 52 weeks (p<0.05) and naïve 64% (16/25)/switch 67% (18/27) at the final follow-up (p<0.01) (Fig. 1). The median grip power at 52 weeks and at the final follow-up improved in both groups. The MTX and PSL doses were decreased at the final follow-up. The Spearman correlation coefficients of the grip power, J-HAQ, and DAS28-ESR were ρ=-0.426 (grip power vs. J-HAQ), ρ=-0.417 (grip power vs. DAS28-ESR), and ρ=0.348 (J-HAQ vs. DAS28-ESR) (p<0.001). Table 2. The Clinical Course of Golimumab. Week 0 Week 52 Final follow-up Median (range) Median (range) p value Median (range) p value DAS28-ESR Naïve 4.31 (3.52-5.25) 2.76 (2.23-4.05) <0.001 2.65 (2.28-3.77) <0.001* Switch 4.27 (3.19-4.89) 2.69 (2.19-3.78) 0.001* 2.89 (2.49-3.88) 0.006* Total 4.27 (3.35-4.27) 2.73 (2.22-3.90) <0.001* 2.73 (2.35-3.77) <0.001* J-HAQ Naïve 0.25 (0.04-0.71) 0.25 (0.05-1.03) 0.593 0.23 (0.04-0.80) 0.771 Switch 0.48 (0.25-0.85) 0.53 (0.23-0.88) 0.490 0.53 (0.10-0.85) 0.608 Total 0.40 (0.05-0.84) 0.40 (0.07-0.93) 0.552 0.30 (0.10-0.84) 0.761 Grip power, mmHg Naïve 138 (104-183) 160 (102-231) <0.001* 183 (100-234) 0.041* Switch 127 (93-168) 158 (112-195) 0.026* 154 (115-190) <0.001* Total 133 (96-179) 158 (107-204) <0.001* 165(105-208) <0.001* Dose of MTX, mg/week Naïve 8.0 (6.0-10.0) 8.0 (3.0-8.5) 0.006* 5.0 (0.0-8.0) <0.001* Switch 5.0 (0.0-8.5) 6.0 (0.0-9.0) 0.091 6.0 (0.0-8.0) 0.007* Total 8.0 (0.0-10.0) 7.0 (1.3-8.8) 0.003* 5.5 (0.0-8.0) <0.001* Dose of PSL, mg/day Naïve 2.3 (0.0-5.0) 2.0 (0.0-5.0) 0.110 2.0 (0.0-3.8) 0.016* Switch 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.040 2.5 (0.0-4.0) 0.004* Total 3.0 (0.0-5.0) 3.0 (0.0-5.0) 0.016* 2.3 (0.0-4.0) <0.001* At 52 weeks and at the final follow-up, each parameter was compared with the baseline value using the Wilcoxon rank sum test adjusted by the Holm method. *: significant difference. Median (range). DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate, J-HAQ: Japanese version of the health assessment questionnaire, MTX: methotrexate, PSL: prednisolone Figure 1. The DAS28-ESR at baseline, 52 weeks, and the final follow-up. The DAS28-ESR classification improved from baseline to 52 weeks and at the final follow-up in both groups (chi-square test: p<0.05). The classification of DAS28-ESR was as follows: remission, DAS28-ESR<2.6; low disease activity, 2.6≤DAS28-ESR<3.2; moderate disease activity, 3.2≤DAS28-ESR≤5.1; high disease activity, DAS28-ESR>5.1. DAS28-ESR: disease activity score 28-erythrocyte sedimentation rate Continuation rate and reason for discontinuation The continuation rate at the final follow-up [median (range): 134 (58-162) weeks] was 22/28 (78.6%) in the naïve group and 26/37 (70.3%) in the switch group. The respective continuation rates of the naïve/switch/total groups calculated using the Kaplan-Meier method were 89.3%/73.0%/80.0% at 52 weeks, 81.1%/73.0%/76.4% at 104 weeks, and 76.3%/68.7%/71.6% at 156 weeks (Fig. 2). No significant difference was detected in the continuation rate between the naïve and switch groups (p=0.829). The continuation rate in patients who were administered MTX was higher than that in patients who were not administered MTX (p=0.001; Fig. 3). On comparing the backgrounds of the naïve and switch groups, patients without MTX had higher median (range) values for the age, C-reactive protein (CRP), ESR, matrix metalloprotease-3 (MMP-3), and rheumatoid factor (RF) at baseline than those with MTX (p<0.05) [patients without MTX vs. patients with MTX, age 73 (69-78) vs. 65 (54-70), CRP 1.65 (0.25-3.23) vs. 0.40 (0.10-1.50), ESR 45 (23-80) vs. 18 (10-28), MMP-3 171 (87-367) vs. 95 (60-194), RF 83 (33-162) vs. 23 (13-106)]. Seventeen patients discontinued the administration of GLM. The reasons for discontinuation were as follows: lack of efficacy (8/65: 12.3%), infection (3/65: 4.6%), and eczema, multiple sclerosis, economic reasons, patient preference for bDMARDs, fracture, and transfer to another hospital in 1 case each (1/65: 1.5%). Ten patients (1 naïve, 9 switch) discontinued GLM within 26 weeks, and 3 discontinued GLM between 26 and 52 weeks. Five patients discontinued GLM within 26 weeks because of a lack of efficacy. No patients discontinued GLM due to remission. Figure 2. Drug continuation rates in the naïve and switch groups. The drug continuation rate showed no significant difference between both groups (log rank: p=0.829). Figure 3. Drug continuation rates in groups administered GLM with and without MTX. The group administered GLM with MTX showed a better drug continuation rate than the group administered GLM without MTX (log rank: p=0.004). GLM: golimumab, MTX: methotrexate Discussion In this study, evaluated the effectiveness and continuation rate of GLM for long-term use in daily practice for patients with RA. We recorded the clinical effect and the continuation rate of GLM in daily practice after 52 weeks. As hypothesized, GLM showed effectiveness not only in bDMARD-naïve patients but also in switch patients. In our institution, 38 patients started GLM 50 mg; however, 20 increased the dose to 100 mg because the 50-mg regimen was inadequate. Increasing the dose improved the DAS; therefore, if the 50-mg regimen is not effective, increasing the dose should be considered. The GO-AFTER study has also reported the clinical efficacy of switching to GLM therapy (14). In agreement with this finding, we found that GLM therapy was effective even for the switch group patients. The remission rate of the naïve/switch group was 40% (10/25)/41% (11/27) at 52 weeks and 44% (11/25)/33% (9/27) at the final follow-up. In the GO-FORTH and GO-FORWARD trials, the rates of remission based on the DAS28-ESR were 32.4-52.2% at 52 weeks, 39.4-75.8% at 104 weeks, and 55.3-61.8% at 156 weeks (2,5). In 2 previous studies, the average age at the baseline was 50 years old, and the average DAS28-ESR at the baseline was 5.5-5.9; these patients showed better remission rates at 52 and 104 weeks than did our patients (2,5). In our trial, the median age of the recruited patients was 69 years old. Thus, the age and age-related complications might have affected the remission rate in our patients. In the GO-AFTER trial, the remission rate of the bDMARD switch group for 52/100/160 weeks was 12.5-15.6% for the 50 mg regimen and 21.5-22.1% for the 100 mg regimen (3). The switch group in our study showed a better remission rate than that in the GO-AFTER study. The higher the remission rate of the switch group in our study may have been due to the better DAS28-ESR at baseline than in the GO-AFTER study. In the present study, we recruited older patients than those described in previous studies (16,31,32), and we therefore believe that the 65 patients that were collected from a single institution with 134 (58-162) weeks of follow-up thus provided valuable information in comparison to previous studies. The J-HAQ was not improved at the final follow-up compared with that at the baseline in the present study, which was inconsistent with our hypothesis. The HAQ score in healthy populations was reported to be 0.49 (33). The GO-FORWARD, GO-FORTH, GO-AFTER, and GO-MONO trials reported improvements in the HAQ-DI (0.37-0.75), and the HAQ-DI baseline values ranged from 0.9 to 1.6 (6,31,32,34). In these 4 clinical trials, the mean age ranged from 50-55 years old, and the mean DAS28-ESR ranged from 5.5-6.3. The age and DAS28-ESR were higher in our study than in those previous trials. Furthermore, in our study, 17/65 (26%) patients were classified as Steinbrocker stage III and 34/65 (52%) as Steinbrocker stage IV. Despite the low J-HAQ score (0.40) of our case series at the baseline, the number of patients in the different Steinbrocker classes were as follows: 1 in class 1, 35 in class 2, 27 in class 3, and 2 in class 4. The Steinbrocker Stage and Class in our study indicated that most patients had some irreversible ADL impairments. Furthermore, in the present study, the grip power was correlated with the J-HAQ score (ρ=-0.426, p<0.01) and DAS28-ESR (ρ=-0.417, p<0.01). Therefore, we consider it necessary to evaluate the grip power when assessing subclinical joint dysfunction. Consistent with our hypothesis, in the present study, treatment with GLM improved the grip power at 52 weeks and at the final follow-up. The use of GLM not only suppressed joint inflammation but also improved the grip power. Uutela et al. (35) reported that the grip power reflected the disease status, such as remission, low/moderate disease activity, and high disease activity. The present study showed that the grip power was correlated with the J-HAQ and DAS28-ESR as continuous variables. Eberhardt et al. reported that the use of TNF inhibitors for more than one year in patients with RA improved the grip power. However, details concerning the TNF inhibitors were not provided. As their study findings were published in 2007, GLM would not have been used (27). Aside from the abovementioned study by Eberhardt et al., there have been no reports showing improvements in the grip power following the use of TNF inhibitors. Our study is thus the first to show an improvement in the grip power in daily practice following GLM use. Improving the grip power may promote the prevention of sarcopenia and frailty in the future. Therefore, measuring the grip strength will likely provide supplemental information about potential ADL impairment. Only 17 patients (26.1%) discontinued the treatment course in our study, indicating a high continuation rate for long-term GLM use. The ANSWER cohort study, comprising 2,494 patients in real clinical practice, reported the retention rates of the following 7 bDMARDs: ABT (75.5%), TCZ (71.5%), GLM (65.6%), ETN (61.2%), certolizumab pegol (60.7%), ADA (58.2%), and IFX (53.4%) at 36 months in adjusted model (36). A systematic review by Svedbom et al. reported that the continuation rate of GLM was higher than that of other TNF inhibitors (9). An important characteristic of GLM is its lower antigenicity than other bDMARDs (37). The low antibody production against GLM is likely associated with its high continuity. Svedbom et al. showed that the respective continuation rates of GLM in real clinical practice at 52/104/156 weeks were 67-76%/49-63%/60% for bDMARD-naïve patients and 47-63%/40-61%/32-54% for bDMARD-switch patients (9). Kondo et al. reported that the continuation rate of GLM after 6 years was 50.3% (38). Compared with these data from real clinical practice, our study findings showed a better continuation rate of GLM in both the naïve and switch groups. However, the systematic review by Svedbom et al. included abstracts from academic conferences, which may have provided inadequate information. Therefore, it would be difficult to precisely analyze the reason for the difference between our findings and those of the systematic review. In our study, patients discontinued the treatment course due to a lack of efficacy (8/65: 12.3%), toxic effects (5/65: 7.7%), and other reasons (4/65: 6.2%). None of the patients discontinued the treatment due to remission. In the ANSWER cohort study, the drug retention rate of GLM in the adjusted model at 36 months was as follows: lack of effectiveness (74.0%), toxic effect (89.1%), and remission (92.5%) (28). Ten patients discontinued GLM within 26 weeks, and 3 discontinued between 26 and 52 weeks. Five patients discontinued GLM because of a lack of efficacy within 26 weeks. Kondo et al. reported that the discontinuation of the treatment course frequently occurred within six months (38). A steady-state plasma concentration can be achieved with 12 weeks of repeated injection of GLM (39), which is longer than that of other TNF-inhibitors (40). The GO-FORTH trial results showed that concurrent use of MTX leads to earlier disease control at three and six months than GLM monotherapy and switching therapy [based on the American College of Rheumatology criteria (41)] for two to five years (2,14,16). Considering the discontinuation of drug administration within 26 weeks in the present study, we suggest that tight control of the RA status within 26 weeks is necessary until GLM exhibits effectiveness, especially in monotherapy and switching therapy groups. The continuation rate was higher in patients who were administered MTX than in those who were not. Concurrent use of MTX with GLM decreases immunogenicity and adverse events (42). The patients without MTX were older and had higher CRP, ESR, MMP-3, and RF values than the patients with MTX; therefore, older patients and those with more severe inflammation are likely to be more adversely affected by continuation of GLM. According to the EULAR recommendation (17), if MTX is not contraindicated, it should be administered. It was challenging to administer MTX to patients without MTX because of other medical complications. Our data also showed a reduction in PSL use at the final follow-up, suggesting that the use of PSL for the short term soon after GLM induction would facilitate a decrease in disease activity until GLM exhibits effectiveness up to 26 weeks. Introduction of the 100-mg GLM regimen would facilitate the early suppression of disease and prevent early drop-out from treatment. Several limitations associated with the present study warrant mention. This was a retrospective study, and the sample size was smaller than that of clinical trials. Furthermore, the concurrent use of csDMARDs (including MTX and other csDMARDs) differed among the naïve and switch groups. The final selection and dosage of bDMARDs was decided by discussion between the patient and the doctor. The initial dose of GLM was decided while considering not only the patient's disease status but also their economic status. Our study lacks adequate data to explore the risk of discontinuation using a multivariate analysis, as 17 patients discontinued the study. Conclusion GLM improved the disease activity and grip power in bDMARD-naïve and switch groups. The concurrent use of MTX with GLM showed a better continuation rate than GLM administration without MTX. This is the first report to show the improvement in the grip power by GLM and to demonstrate that the use of GLM can prevent sarcopenia in the future. We also found that the grip power was correlated with the J-HAQ and DAS28-ESR. Our findings concerning the effects of GLM may facilitate further studies on effective RA treatment regimens. Author's disclosure of potential Conflicts of Interest (COI). Satoshi Ito: Honoraria, Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Jansen Pharma and Mitsubishi Tanabe. Hajime Ishikawa: Honoraria, Astellas, Chugai, Gilead Sciences and Corrona.	3 mg (milligrams).	DrugDosage	CC BY-NC-ND	33250460	18,599,924	2021-05-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetes mellitus'.	Clinical Characteristics and Treatment Response With Checkpoint Inhibitors in Malignant Melanoma of the Vulva and Vagina. OBJECTIVE The aims of the study were to assess the clinical and histopathological characteristics of a comprehensive cohort of women with vulvovaginal melanoma (VVM) treated at our institution and to study the treatment response of checkpoint inhibitors in this patient cohort. METHODS This is a retrospective study of women with invasive VVM treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, over a period of 15 years. Clinical and histopathological characteristics, treatment, as well as treatment-related outcome were analyzed in 32 women. Treatment response was evaluated retrospectively using the "response criteria for use in trials testing immunotherapeutics" (iRECIST). The objective response rate was defined as the proportion of patients with complete or partial response based on the best overall response. RESULTS At a median follow-up of 37.8 months (5.8-110.4), 26 women (81.3%) had disease progression and 16 (50%) died. Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors. Ten additional cases were identified from previously published reports. The best objective response rate for immune checkpoint inhibitors was 30.4% (95% CI = 11.6%-49.2%) and the clinical benefit rate was 52.2% (95% CI = 31.8%-72.6%). The clinical benefit rate was significantly better for programmed cell death protein 1 inhibitors (or a combination) compared with ipilimumab alone (Fisher exact, p = .023). Grade 3/4 adverse events were observed in 3 (13.0%) of the 23 patients. CONCLUSIONS Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective in the treatment of metastatic melanoma in this patient cohort. Melanomas of the vulva and vagina account for 1% of all melanomas diagnosed in women and for 5.3% of all vulvar and 5.5% of all vaginal malignancies.1 Genital tract melanomas are commonly categorized as mucosal melanomas, but this has been questioned by studies showing different mutational characteristics suggesting that vulvovaginal melanomas (VVMs) may be classified as a unique subclass.2–5 Data on VVMs are scarce, and to date, only 1 prospective study has been completed: The Gynecologic Oncology Group 73 protocol suggested that the American Joint Committee on Cancer (AJCC) staging was the best predictor for survival and Breslow’s depth of invasion and lymphovascular space invasion were predictive of lymph node metastases.6 In a population-based study, we have recently shown that VVMs have a particularly poor prognosis with a median overall survival of 53 months in vulvar melanoma and 16 months in vaginal melanoma with no important change in survival over time.1 The treatment landscape of advanced and metastatic melanoma has drastically changed with the introduction of immune checkpoint inhibitors. Trials with the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor ipilimumab and the programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab have shown profound improvements of survival in patients with unresectable or metastatic melanoma.7–9 In a pooled analyses of clinical trials, mucosal melanomas, however, had lower response rates to nivolumab and pembrolizumab compared with cutaneous melanomas.10,11 Data for VVMs are scarce. The aims of this study are to describe clinical characteristics of a comprehensive cohort of women with VVM treated at our institution and to assess the treatment response of immune checkpoint inhibitors in this patient cohort. METHODS Study Population This is a retrospective single-center cohort study of women with invasive melanoma of the vulva or vagina treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada. The study protocol was approved by the institutional review ethics board (UHN 19-5620). All women with histologically confirmed invasive vulvar or vaginal melanoma diagnosed over a period of 15 years (2004–2018) were included and all cases were reviewed by an expert pathologist at the time of initial presentation; women with melanoma in situ without invasive components were not included. Vulvar melanomas were staged according to the AJCC staging classification in the eighth edition, and vaginal melanomas were classified as local, regional, or distant.12 Demographic data, Eastern Cooperative Oncology Group performance (ECOG) score, histopathology, type of surgery, lymph node assessment, adjuvant treatment, recurrence, treatment details for recurrent disease, and vital status were extracted from the electronic patient records. Programmed death-ligand 1 was not routinely tested in our patient cohort. Selection for immunotherapy was based on availability. Treatment response was evaluated retrospectively using the “response criteria for use in trials testing immunotherapeutics” (iRECIST).13 The objective response rate (ORR) was defined as the proportion of patients with complete (iCR) or partial response (iPR) based on the best overall response (iBOR).13 The clinical benefit rate (CBR) was defined as the proportion of patients with iCR, iPR, or stable disease (iSD). An iSD was assigned if no disease progression occurred for at least 2 months. Adverse events were categorized using the common terminology criteria for adverse events version 5.0.14 The treatment response of immune checkpoint inhibitors was analyzed in our cohort. In addition, treatment response from previously published case series and case reports was identified from PubMed using the search terms “ipilimumab,” “nivolumab,” or “pembrolizumab” in combination with “vulva” or “vagina,” and a separate analysis was performed for our cohort and the combined cohort. Reports without information on treatment response were not included. Statistical Analyses Descriptive statistics was used to report demographic data. Continuous variables were compared using the Student t test, Mann-Whitney test, or Wilcoxon test, as appropriate. Categorical data were compared using the Fisher exact test. Progression-free survival (PFS) and overall survival (OS) for the comprehensive cohort were calculated from the date of diagnosis to date of progression or death (PFS) and date of diagnosis to date of death (OS). Progression-free survival and OS for the subgroup analysis of immune checkpoint inhibitors were calculated from the date of treatment initiation to the date of progression or death, respectively. The Kaplan-Meier method with log-rank test was used to analyze PFS and OS. The 2- and 5-year survival rates were calculated using the Kaplan-Meier method. Statistical analysis was performed using SPSS Version 26, IBM, Armonk. A p value of less than .05 was considered statistically significant, all tests were 2-sided. Role of the Funding Source I.W.-W. is supported by a grant from the Austrian Science Fund (Project Number J 4382-B) to fund her fellowship at the Division of Dermatology, Department of Medicine, University of Toronto, Ontario, Canada. No external funding was used in the preparation of this manuscript. RESULTS Patient Characteristics In total, 32 women with invasive vulvar (n = 28) and vaginal (n = 4) melanoma were treated at our institution over a period of 15 years and included in our study. Demographic and clinical characteristics are shown in Table 1. The mean age at diagnosis was 66 years, and a significant proportion of patients was diagnosed with advanced disease stage, tumor thickness of greater than 4 mm, ulcerations, and high mitotic count; 31.3% already reported symptoms from melanoma including bleeding, pruritus, and pain at the time of diagnosis. Histologic characteristics are shown in Table 2. BRAF was tested in 25 patients and was positive in 2 (8.0%), cKIT was positive in 3 (13.6%) of the 22 patients tested, and NRAS mutations were detected in 2 (13.3%) of the 15 patients tested. A mutation in SF3B1 was found in 2 patients and 1 woman was found to have a PTEN mutation. TABLE 1 Patient Characteristics Parameter Age at diagnosis, y Mean ± SD 66.3 ± 14.0 Median (range) 66.0 (40–96) Pregnancy history Gravida 2 (0–3) Para 2 (0–3) ECOG performance status at diagnosis ECOG 0 23 (71.9%) ECOG 1 6 (18.8%) ECOG 2 2 (6.3%) ECOG 3 1 (3.1%) History of previous malignancy History of melanoma 2 (6.3%) History of other malignancy 7 (21.9%) Tumor stage at diagnosis Vulvar melanoma (n = 28) AJCC stage I 1 (3.6%) AJCC stage II 13 (46.4%) AJCC stage III 11 (39.3%) AJCC stage IV 3 (10.7%) Vaginal melanoma (n = 4) local 0 (0%) regional 4 (100%) distant 0 (0%) Reported symptoms Any symptoms reported 10 (31.3%) Pruritus 4 (12.5%) Bleeding 8 (25.0%) Pain 4 (12.5%) Organ involvement Labia majora 22 (68.8%) Labia minora 15 (46.9%) Clitoris 10 (31.1%) Urethra 4 (12.5%) Anus 0 (0%) Surgery Radical local excision 31 (96.9%) Exenteration 1 (3.1%) Surgical lymph node assessment Performed 27 (84.4%) Nodal metastases 14 (51.9%) Negative lymph nodes 13 (48.1%) TABLE 2 Histologic Characteristics Characteristics Tumor thickness, mm Median (range) 8 (1.1–68) ≤1.00 0 (0%) 1.01–2.00 4 (12.9%) 2.01–4.00 7 (22.6%) >4.00 20 (62.5%) Ulceration Present 24 (77.4%) Absent 7 (21.9%) Mitotic count, mitoses/mm2 Median (range) 8 (0–50) 0 1 (3.4%) 1 1 (3.4%) 2–10 14 (48.3%) >10 13 (44.8%) All women underwent surgery, and the lymph node status was surgically evaluated in 84.4% of all patients and in 88.0% of those with nonmetastatic vulvar melanoma. Adjuvant systemic treatment was given in 5 patients (15.6%): adjuvant interferon α in 3 and nivolumab in 2 patients, and their outcome is reported hereinafter. Outcome At a median follow-up of 37.8 months (5.8–110.4), 26 (81.3%) women had disease progression and 16 (50%) died. The median PFS was 17.7 months (95% CI = 5.5–29.8 months), and the 2- and 5-year PFS rates were 35.4% and 23.2%, respectively. The median OS was 59.1 months (95% CI = 23.6–94.5 months), and the 2- and 5-year OS rates were 71.1% and 45.6%, respectively. The 2-year PFS rate by the AJCC stage in vulvar melanoma was as follows: stage I, 100%; stage II, 35.9%; stage III, 42.4%; stage IV, 33.3%; and in the 4 patients with regional vaginal melanoma, 0% (p = .126). Fifteen (51.7%) of the 29 nonmetastatic patients at diagnosis developed distant metastases with a median time to metastatic disease of 39.5 months (95% CI = 0–84.2 months). Two patients received adjuvant nivolumab: 1 patient with vaginal melanoma developed brain metastases during adjuvant treatment with nivolumab. She was treated with stereotactic radiation and switched to pembrolizumab. The best overall response was iSD, but she ultimately progressed and died of melanoma (see Table 3, PMH05). The second patient receiving adjuvant nivolumab had vulvar melanoma AJCC stage IIIC. She had a local recurrence after 77 months, which was excised, and she has now been recurrence-free for 8 months. TABLE 3 Characteristics of Women With Malignant Melanoma of the Vulva or Vagina Receiving Immune Checkpoint Inhibitors (Combining Our Own Patient Cohort and Patients Identified From the Literature) Patient Site Stage at treatment initiationa (metastases) Prior systemic therapy Prior XRT, Site Immunotherapy iBOR PFSb irAEs OSc Vital status PMH01 Vulva IIIC, unresectable None None Pembrolizumab iCPD 2 None 18 Alive with disease PMH02 Vulva IV (lung) None None Ipilimumab + nivolumab iSD 18 Uveitis G1, peripheral sensory neuropathy G3 18 Alive with disease PMH03 Vulva IV (liver) None None Ipilimumab + nivolumab iCPD 1 None 1 Died of disease PMH04 Vulva IV (liver) None None Nivolumab iPR 15 Hepatitis G1 15 Alive with disease PMH05 Vagina Distant (brain) Nivolumab, adjuvant None Pembrolizumab iSD 4 None 16 Died of disease PMH06 Vulva IV (lung) None None Ipilimumab iCR 56 None 56 Alive with NED PMH07 Vulva IV (lung, liver) Interferon, adjuvant None 1. Ipilimumab iCPD 3 Maculopapular exanthema G1, Hepatitis G1 17 Died of disease 2. Pembrolizumab iSD 4 None PMH08 Vulva IV (liver) None Liver 1. Ipilimumab iCPD 3 Maculopapular exanthema G1 50 Alive with disease 2. Pembrolizumab iPR 9 None PMH09 Vulva IV (lung, brain) Carboplatin/paclitaxel Brain Ipilimumab iCPD 3 None 6 Died of disease PMH10 Vulva IV (lung) Dacarbazine Groin 1. Ipilimumab iCPD 3 None 87 Alive with NED 2. Pembrolizumab iCR 77 Hyperthyroidism G2, DM G3, Erythema nodosum G1 PMH11 Vulva IV (lung, bone) None Vulva + groin Ipilimumab iCPD 1 None 1 Died of disease PMH12 Vulva IV (lung, abdomen) Carboplatin/paclitaxel Vulva + groin 1. Ipilimumab iCPD 3 None 16 Died of disease 2. Pembrolizumab iCPD 3 None PMH13 Vulva IV (lung, abdomen, soft tissue) Carboplatin/paclitaxel Abdomen + groin Ipilimumab iSD 2 None 13 Died of disease Indini115 Vulva IV (lung) CVD None Ipilimumab iCPD 4 None 7 Died of disease Indini215 Vulva IV (lung, bone) None None Pembrolizumab iPR 10 Arthralgia G2, hypothyroidism G2 10 Alive with disease Indini315 Vagina Distant (liver) None None Pembrolizumab iCPD 2 None 4 Alive with disease Indini415 Vagina Distant (n.s.) None Vagina Nivolumab iSD 4 Cutaneous rash G1 4 Alive with disease Indini515 Vagina Distant (liver, pancreas, soft tissues, bone) None None Ipilimumab iCPD 3 None 7 Died of disease Indini615 Vagina Distant (lung) Dacarbazine None Ipilimumab iCPD 3 None 18 Died of disease Daix116 Vagina Regional, unresectable None None Nivolumab iCR 8 Pruritus G1 8 Alive with NED Anko117 Vagina Distant (liver, lung, bone) None None Nivolumab iPR/iCR 17 Thyroiditis, n.s. 17 Alive Komatsu-Fujii118 Vagina Distant (lung) None None 1. Nivolumab iCPD n.s. n.s. n.s. Alive with disease 2. Pembrolizumab iCPD n.s. n.s. 3. Ipilimumab iCPD n.s. n.s. Inoue119 Vagina Distant (brain) None Brain Nivolumab iCPD 2 Hepatitis G3 n.s. Alive with disease Characteristics of the 13 patients treated our institution (PMH1–PMH13) and 10 additional previously published cases. aStage at initiation of treatment with immune checkpoint inhibitor, AJCC stage for vulvar melanomas and local/regional/distant for vaginal melanomas. bPFS in months defined from treatment initiation with immune checkpoint inhibitor to date of progression or death. cOS in months defined from treatment initiation with first immune checkpoint inhibitor to date of last follow-up or death. CVD indicates cisplatin-vinblastine-dacarbazine; DM, diabetes mellitus; G, grade; iCPD, confirmed progressive disease; irAEs, immune-related adverse events; NED, no evidence of disease; n.s., not specified; XRT, radiation therapy. Treatment Response of Immune Checkpoint Inhibitors in Unresectable or Metastatic Melanoma Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors, and 4 patients were initially treated with ipilimumab and switched to a PD-1 inhibitor after treatment failure. The best overall ORR with immunotherapy in the 13 patients was 30.8% (95% CI = 5.7%–55.9%), and the CBR was 61.5% (95% CI = 35.1%–88.0%). The median PFS was 4.0 months (95% CI = 2.3–5.7 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). Ipilimumab was given in 8 patients; the ORR was 12.5% (95% CI = 0%–35.4%), and the CBR was 25.0% (95% CI = 0%–55.0%). Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were given in 9 patients; the ORR was 33.3% (95% CI = 2.5%–64.1%), and the CBR was 66.7% (95% CI = 35.9%–97.5%). In addition, 13 patients with VVM receiving immune checkpoint inhibitors were identified from previously published cases in the literature15–20; 10 patients with metastatic or unresectable VVM were included (see Table 3); 3 patients, who received neoadjuvant ipilimumab and radiation and subsequently underwent surgery, were not included.20 The best overall ORR with immune checkpoint inhibitors in the combined cohort of the 23 patients was 30.4% (95% CI = 11.6%–49.2%), and the CBR was 52.2% (95% CI = 31.8%–72.6%). The median PFS was 4.0 months (95% CI = 2.7–5.3 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). The ORR for ipilimumab alone was 8.3% (95% CI = 0%–24%) compared with 37.5% (95% CI = 13.8%–61.2%, Fisher exact, p = .184) for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The CBR was 16.7% (95% CI = 0%–37.8%) for ipilimumab compared with 62.5% (95% CI = 38.8%–86.2%, Fisher exact, p = .023) for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The median PFS for ipilimumab alone was 3.0 months (95% CI = 2.6–3.4 months) compared with 9.0 months (95% CI = 1.9–16.1 months, p = .062) for PD-1 inhibitors or the combination of CTLA-4 and PD-1 inhibitors. Severe adverse events (grade 3/4) were observed in 2 (15.4%) of the 13 patients in our cohort and 3 (13.0%) of the 23 patients in the total cohort. DISCUSSION In this study, we report the clinical characteristics of VVM and the treatment response to immune checkpoint inhibitors in a comprehensive cohort. Most women were diagnosed in advanced disease stages with poor prognostic indicators. Half of the nonmetastatic patients undergoing surgical lymph node assessment had lymph node metastases, and most our patients had a high mitotic count, both of which were recently shown to be important independent predictors for survival in women with VVMs.1,21 More than 80% of our cohort had disease recurrence or progression with a 2- and 5-year PFS rate of 35.4% and 23.2%, respectively. More than 50% of the women, who were free of distant metastases at diagnosis, developed metastatic disease. Therefore, women with VVM represent a high-risk group. Consistent with previous reports and unlike in cutaneous melanomas, only a small proportion of patients had BRAF mutations, limiting the treatment options with BRAF/MEK inhibitors.3,4 cKIT mutations were observed 14% and NRAS mutations in 13%; 2 patients were found to have a mutation in SF3B1, a mutation that was recently found to be more prevalent in VVMs and may be associated with worse outcome.22 The introduction of immune checkpoint inhibitors has led to an enormous progress in melanoma treatment and checkpoint inhibitors are now United States Food and Drug Administration and European Medicines Agency approved in the adjuvant and metastatic setting. The mechanism of action of CTLA-4 and PD-1 inhibitors is shown in Figure 1. For ipilimumab, we have observed an ORR of 8.3% and a CBR of 16.7% with median PFS of 3.0 months. The ORR is notably lower compared with 21.2% in cutaneous melanoma but identical to the recently reported response rate in mucosal melanomas combining data from 6 clinical trials (2 phase I trials: CA209-00323 and CA209-03824; 1 phase II trial: CheckMate 06925; and 3 phase III trials: CheckMate 066,26 CheckMate 037,27 and CheckMate 0678,10). FIGURE 1 Mechanism of action of immune checkpoint inhibitors in malignant melanoma of the vulva and vagina. Antigen presenting cells present the tumor antigen to T cells through MHC-II but also express inhibitory signals (CD80/86). CD80/86 binds to CTLA-4 and prevents T-cell activation. Ipilimumab, a monoclonal antibody that binds and inhibits CTLA-4, prevents this inhibition resulting in T-cell activation. Similarly, tumor cells express PD-L1 that binds to PD-1 receptors expressed on T cells, resulting in T-cell anergy. nivolumab and pembrolizumab (PD-1 inhibitors) bind PD-1 resulting in T-cell activation. APC, antigen presenting cells; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; MHC-I, major histocompatibility complex 1; MHC-II, major histocompatibility complex 2; PD-L1, programmed death-ligand 1; TCR, T-cell receptor. For PD-1 or a combination of PD-1 and CTLA-4 inhibitors, the ORR was 37.5% and the CBR was 62.5% with a median PFS of 9.0 months. This is again lower compared with the ORR of 60.4% reported for a combination of nivolumab and ipilimumab10 but comparable with 40.9% for nivolumab10 and 33.0% for pembrolizumab (combining 3 clinical trials, KEYNOTE-001,28 KEYNOTE-002,29 and KEYNOTE-0069,11 in cutaneous melanoma). Severe adverse events were observed in 15.4% of our cohort, which is comparable with the rate observed in mucosal melanomas.10 Strengths and Limitations This study investigates a large series of well-described cases of vulvar and vaginal melanoma diagnosed and treated at a comprehensive cancer center. We report clinical characteristics, outcome and treatment response with immune checkpoint inhibitors. The study is, however, limited by its retrospective design. Furthermore, including case reports into the analysis of treatment response adds the risk of publication bias. We have therefore analyzed our own series including all patients with VVM treated at our institution separately, and no distortion of the response rates was observed when adding the additional 10 cases previously published in the literature. CONCLUSIONS Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective with a complete or partial response being observed in approximately one third of women with locally unresectable or metastatic VVM. Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were associated with a significantly higher CBR and a trend toward longer progression-free survival compared with CTLA-4 inhibitors alone. The authors have declared they have no conflicts of interest. I.W.-W. is supported by a grant from the Austrian Science Fund (Project Number J 4382-B). The study was approved by the institutional review ethics board (UHN 19-5620). C.W. and I.W.-W. did the study conception, data acquisition and analysis, interpretation of data and original draft of the manuscript, review, and editing. S.L. did the investigation, methodology, review, and editing of the manuscript.	IPILIMUMAB, PEMBROLIZUMAB	DrugsGivenReaction	CC BY	33252450	18,648,560	2021-04-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Erythema nodosum'.	Clinical Characteristics and Treatment Response With Checkpoint Inhibitors in Malignant Melanoma of the Vulva and Vagina. OBJECTIVE The aims of the study were to assess the clinical and histopathological characteristics of a comprehensive cohort of women with vulvovaginal melanoma (VVM) treated at our institution and to study the treatment response of checkpoint inhibitors in this patient cohort. METHODS This is a retrospective study of women with invasive VVM treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, over a period of 15 years. Clinical and histopathological characteristics, treatment, as well as treatment-related outcome were analyzed in 32 women. Treatment response was evaluated retrospectively using the "response criteria for use in trials testing immunotherapeutics" (iRECIST). The objective response rate was defined as the proportion of patients with complete or partial response based on the best overall response. RESULTS At a median follow-up of 37.8 months (5.8-110.4), 26 women (81.3%) had disease progression and 16 (50%) died. Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors. Ten additional cases were identified from previously published reports. The best objective response rate for immune checkpoint inhibitors was 30.4% (95% CI = 11.6%-49.2%) and the clinical benefit rate was 52.2% (95% CI = 31.8%-72.6%). The clinical benefit rate was significantly better for programmed cell death protein 1 inhibitors (or a combination) compared with ipilimumab alone (Fisher exact, p = .023). Grade 3/4 adverse events were observed in 3 (13.0%) of the 23 patients. CONCLUSIONS Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective in the treatment of metastatic melanoma in this patient cohort. Melanomas of the vulva and vagina account for 1% of all melanomas diagnosed in women and for 5.3% of all vulvar and 5.5% of all vaginal malignancies.1 Genital tract melanomas are commonly categorized as mucosal melanomas, but this has been questioned by studies showing different mutational characteristics suggesting that vulvovaginal melanomas (VVMs) may be classified as a unique subclass.2–5 Data on VVMs are scarce, and to date, only 1 prospective study has been completed: The Gynecologic Oncology Group 73 protocol suggested that the American Joint Committee on Cancer (AJCC) staging was the best predictor for survival and Breslow’s depth of invasion and lymphovascular space invasion were predictive of lymph node metastases.6 In a population-based study, we have recently shown that VVMs have a particularly poor prognosis with a median overall survival of 53 months in vulvar melanoma and 16 months in vaginal melanoma with no important change in survival over time.1 The treatment landscape of advanced and metastatic melanoma has drastically changed with the introduction of immune checkpoint inhibitors. Trials with the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor ipilimumab and the programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab have shown profound improvements of survival in patients with unresectable or metastatic melanoma.7–9 In a pooled analyses of clinical trials, mucosal melanomas, however, had lower response rates to nivolumab and pembrolizumab compared with cutaneous melanomas.10,11 Data for VVMs are scarce. The aims of this study are to describe clinical characteristics of a comprehensive cohort of women with VVM treated at our institution and to assess the treatment response of immune checkpoint inhibitors in this patient cohort. METHODS Study Population This is a retrospective single-center cohort study of women with invasive melanoma of the vulva or vagina treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada. The study protocol was approved by the institutional review ethics board (UHN 19-5620). All women with histologically confirmed invasive vulvar or vaginal melanoma diagnosed over a period of 15 years (2004–2018) were included and all cases were reviewed by an expert pathologist at the time of initial presentation; women with melanoma in situ without invasive components were not included. Vulvar melanomas were staged according to the AJCC staging classification in the eighth edition, and vaginal melanomas were classified as local, regional, or distant.12 Demographic data, Eastern Cooperative Oncology Group performance (ECOG) score, histopathology, type of surgery, lymph node assessment, adjuvant treatment, recurrence, treatment details for recurrent disease, and vital status were extracted from the electronic patient records. Programmed death-ligand 1 was not routinely tested in our patient cohort. Selection for immunotherapy was based on availability. Treatment response was evaluated retrospectively using the “response criteria for use in trials testing immunotherapeutics” (iRECIST).13 The objective response rate (ORR) was defined as the proportion of patients with complete (iCR) or partial response (iPR) based on the best overall response (iBOR).13 The clinical benefit rate (CBR) was defined as the proportion of patients with iCR, iPR, or stable disease (iSD). An iSD was assigned if no disease progression occurred for at least 2 months. Adverse events were categorized using the common terminology criteria for adverse events version 5.0.14 The treatment response of immune checkpoint inhibitors was analyzed in our cohort. In addition, treatment response from previously published case series and case reports was identified from PubMed using the search terms “ipilimumab,” “nivolumab,” or “pembrolizumab” in combination with “vulva” or “vagina,” and a separate analysis was performed for our cohort and the combined cohort. Reports without information on treatment response were not included. Statistical Analyses Descriptive statistics was used to report demographic data. Continuous variables were compared using the Student t test, Mann-Whitney test, or Wilcoxon test, as appropriate. Categorical data were compared using the Fisher exact test. Progression-free survival (PFS) and overall survival (OS) for the comprehensive cohort were calculated from the date of diagnosis to date of progression or death (PFS) and date of diagnosis to date of death (OS). Progression-free survival and OS for the subgroup analysis of immune checkpoint inhibitors were calculated from the date of treatment initiation to the date of progression or death, respectively. The Kaplan-Meier method with log-rank test was used to analyze PFS and OS. The 2- and 5-year survival rates were calculated using the Kaplan-Meier method. Statistical analysis was performed using SPSS Version 26, IBM, Armonk. A p value of less than .05 was considered statistically significant, all tests were 2-sided. Role of the Funding Source I.W.-W. is supported by a grant from the Austrian Science Fund (Project Number J 4382-B) to fund her fellowship at the Division of Dermatology, Department of Medicine, University of Toronto, Ontario, Canada. No external funding was used in the preparation of this manuscript. RESULTS Patient Characteristics In total, 32 women with invasive vulvar (n = 28) and vaginal (n = 4) melanoma were treated at our institution over a period of 15 years and included in our study. Demographic and clinical characteristics are shown in Table 1. The mean age at diagnosis was 66 years, and a significant proportion of patients was diagnosed with advanced disease stage, tumor thickness of greater than 4 mm, ulcerations, and high mitotic count; 31.3% already reported symptoms from melanoma including bleeding, pruritus, and pain at the time of diagnosis. Histologic characteristics are shown in Table 2. BRAF was tested in 25 patients and was positive in 2 (8.0%), cKIT was positive in 3 (13.6%) of the 22 patients tested, and NRAS mutations were detected in 2 (13.3%) of the 15 patients tested. A mutation in SF3B1 was found in 2 patients and 1 woman was found to have a PTEN mutation. TABLE 1 Patient Characteristics Parameter Age at diagnosis, y Mean ± SD 66.3 ± 14.0 Median (range) 66.0 (40–96) Pregnancy history Gravida 2 (0–3) Para 2 (0–3) ECOG performance status at diagnosis ECOG 0 23 (71.9%) ECOG 1 6 (18.8%) ECOG 2 2 (6.3%) ECOG 3 1 (3.1%) History of previous malignancy History of melanoma 2 (6.3%) History of other malignancy 7 (21.9%) Tumor stage at diagnosis Vulvar melanoma (n = 28) AJCC stage I 1 (3.6%) AJCC stage II 13 (46.4%) AJCC stage III 11 (39.3%) AJCC stage IV 3 (10.7%) Vaginal melanoma (n = 4) local 0 (0%) regional 4 (100%) distant 0 (0%) Reported symptoms Any symptoms reported 10 (31.3%) Pruritus 4 (12.5%) Bleeding 8 (25.0%) Pain 4 (12.5%) Organ involvement Labia majora 22 (68.8%) Labia minora 15 (46.9%) Clitoris 10 (31.1%) Urethra 4 (12.5%) Anus 0 (0%) Surgery Radical local excision 31 (96.9%) Exenteration 1 (3.1%) Surgical lymph node assessment Performed 27 (84.4%) Nodal metastases 14 (51.9%) Negative lymph nodes 13 (48.1%) TABLE 2 Histologic Characteristics Characteristics Tumor thickness, mm Median (range) 8 (1.1–68) ≤1.00 0 (0%) 1.01–2.00 4 (12.9%) 2.01–4.00 7 (22.6%) >4.00 20 (62.5%) Ulceration Present 24 (77.4%) Absent 7 (21.9%) Mitotic count, mitoses/mm2 Median (range) 8 (0–50) 0 1 (3.4%) 1 1 (3.4%) 2–10 14 (48.3%) >10 13 (44.8%) All women underwent surgery, and the lymph node status was surgically evaluated in 84.4% of all patients and in 88.0% of those with nonmetastatic vulvar melanoma. Adjuvant systemic treatment was given in 5 patients (15.6%): adjuvant interferon α in 3 and nivolumab in 2 patients, and their outcome is reported hereinafter. Outcome At a median follow-up of 37.8 months (5.8–110.4), 26 (81.3%) women had disease progression and 16 (50%) died. The median PFS was 17.7 months (95% CI = 5.5–29.8 months), and the 2- and 5-year PFS rates were 35.4% and 23.2%, respectively. The median OS was 59.1 months (95% CI = 23.6–94.5 months), and the 2- and 5-year OS rates were 71.1% and 45.6%, respectively. The 2-year PFS rate by the AJCC stage in vulvar melanoma was as follows: stage I, 100%; stage II, 35.9%; stage III, 42.4%; stage IV, 33.3%; and in the 4 patients with regional vaginal melanoma, 0% (p = .126). Fifteen (51.7%) of the 29 nonmetastatic patients at diagnosis developed distant metastases with a median time to metastatic disease of 39.5 months (95% CI = 0–84.2 months). Two patients received adjuvant nivolumab: 1 patient with vaginal melanoma developed brain metastases during adjuvant treatment with nivolumab. She was treated with stereotactic radiation and switched to pembrolizumab. The best overall response was iSD, but she ultimately progressed and died of melanoma (see Table 3, PMH05). The second patient receiving adjuvant nivolumab had vulvar melanoma AJCC stage IIIC. She had a local recurrence after 77 months, which was excised, and she has now been recurrence-free for 8 months. TABLE 3 Characteristics of Women With Malignant Melanoma of the Vulva or Vagina Receiving Immune Checkpoint Inhibitors (Combining Our Own Patient Cohort and Patients Identified From the Literature) Patient Site Stage at treatment initiationa (metastases) Prior systemic therapy Prior XRT, Site Immunotherapy iBOR PFSb irAEs OSc Vital status PMH01 Vulva IIIC, unresectable None None Pembrolizumab iCPD 2 None 18 Alive with disease PMH02 Vulva IV (lung) None None Ipilimumab + nivolumab iSD 18 Uveitis G1, peripheral sensory neuropathy G3 18 Alive with disease PMH03 Vulva IV (liver) None None Ipilimumab + nivolumab iCPD 1 None 1 Died of disease PMH04 Vulva IV (liver) None None Nivolumab iPR 15 Hepatitis G1 15 Alive with disease PMH05 Vagina Distant (brain) Nivolumab, adjuvant None Pembrolizumab iSD 4 None 16 Died of disease PMH06 Vulva IV (lung) None None Ipilimumab iCR 56 None 56 Alive with NED PMH07 Vulva IV (lung, liver) Interferon, adjuvant None 1. Ipilimumab iCPD 3 Maculopapular exanthema G1, Hepatitis G1 17 Died of disease 2. Pembrolizumab iSD 4 None PMH08 Vulva IV (liver) None Liver 1. Ipilimumab iCPD 3 Maculopapular exanthema G1 50 Alive with disease 2. Pembrolizumab iPR 9 None PMH09 Vulva IV (lung, brain) Carboplatin/paclitaxel Brain Ipilimumab iCPD 3 None 6 Died of disease PMH10 Vulva IV (lung) Dacarbazine Groin 1. Ipilimumab iCPD 3 None 87 Alive with NED 2. Pembrolizumab iCR 77 Hyperthyroidism G2, DM G3, Erythema nodosum G1 PMH11 Vulva IV (lung, bone) None Vulva + groin Ipilimumab iCPD 1 None 1 Died of disease PMH12 Vulva IV (lung, abdomen) Carboplatin/paclitaxel Vulva + groin 1. Ipilimumab iCPD 3 None 16 Died of disease 2. Pembrolizumab iCPD 3 None PMH13 Vulva IV (lung, abdomen, soft tissue) Carboplatin/paclitaxel Abdomen + groin Ipilimumab iSD 2 None 13 Died of disease Indini115 Vulva IV (lung) CVD None Ipilimumab iCPD 4 None 7 Died of disease Indini215 Vulva IV (lung, bone) None None Pembrolizumab iPR 10 Arthralgia G2, hypothyroidism G2 10 Alive with disease Indini315 Vagina Distant (liver) None None Pembrolizumab iCPD 2 None 4 Alive with disease Indini415 Vagina Distant (n.s.) None Vagina Nivolumab iSD 4 Cutaneous rash G1 4 Alive with disease Indini515 Vagina Distant (liver, pancreas, soft tissues, bone) None None Ipilimumab iCPD 3 None 7 Died of disease Indini615 Vagina Distant (lung) Dacarbazine None Ipilimumab iCPD 3 None 18 Died of disease Daix116 Vagina Regional, unresectable None None Nivolumab iCR 8 Pruritus G1 8 Alive with NED Anko117 Vagina Distant (liver, lung, bone) None None Nivolumab iPR/iCR 17 Thyroiditis, n.s. 17 Alive Komatsu-Fujii118 Vagina Distant (lung) None None 1. Nivolumab iCPD n.s. n.s. n.s. Alive with disease 2. Pembrolizumab iCPD n.s. n.s. 3. Ipilimumab iCPD n.s. n.s. Inoue119 Vagina Distant (brain) None Brain Nivolumab iCPD 2 Hepatitis G3 n.s. Alive with disease Characteristics of the 13 patients treated our institution (PMH1–PMH13) and 10 additional previously published cases. aStage at initiation of treatment with immune checkpoint inhibitor, AJCC stage for vulvar melanomas and local/regional/distant for vaginal melanomas. bPFS in months defined from treatment initiation with immune checkpoint inhibitor to date of progression or death. cOS in months defined from treatment initiation with first immune checkpoint inhibitor to date of last follow-up or death. CVD indicates cisplatin-vinblastine-dacarbazine; DM, diabetes mellitus; G, grade; iCPD, confirmed progressive disease; irAEs, immune-related adverse events; NED, no evidence of disease; n.s., not specified; XRT, radiation therapy. Treatment Response of Immune Checkpoint Inhibitors in Unresectable or Metastatic Melanoma Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors, and 4 patients were initially treated with ipilimumab and switched to a PD-1 inhibitor after treatment failure. The best overall ORR with immunotherapy in the 13 patients was 30.8% (95% CI = 5.7%–55.9%), and the CBR was 61.5% (95% CI = 35.1%–88.0%). The median PFS was 4.0 months (95% CI = 2.3–5.7 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). Ipilimumab was given in 8 patients; the ORR was 12.5% (95% CI = 0%–35.4%), and the CBR was 25.0% (95% CI = 0%–55.0%). Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were given in 9 patients; the ORR was 33.3% (95% CI = 2.5%–64.1%), and the CBR was 66.7% (95% CI = 35.9%–97.5%). In addition, 13 patients with VVM receiving immune checkpoint inhibitors were identified from previously published cases in the literature15–20; 10 patients with metastatic or unresectable VVM were included (see Table 3); 3 patients, who received neoadjuvant ipilimumab and radiation and subsequently underwent surgery, were not included.20 The best overall ORR with immune checkpoint inhibitors in the combined cohort of the 23 patients was 30.4% (95% CI = 11.6%–49.2%), and the CBR was 52.2% (95% CI = 31.8%–72.6%). The median PFS was 4.0 months (95% CI = 2.7–5.3 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). The ORR for ipilimumab alone was 8.3% (95% CI = 0%–24%) compared with 37.5% (95% CI = 13.8%–61.2%, Fisher exact, p = .184) for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The CBR was 16.7% (95% CI = 0%–37.8%) for ipilimumab compared with 62.5% (95% CI = 38.8%–86.2%, Fisher exact, p = .023) for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The median PFS for ipilimumab alone was 3.0 months (95% CI = 2.6–3.4 months) compared with 9.0 months (95% CI = 1.9–16.1 months, p = .062) for PD-1 inhibitors or the combination of CTLA-4 and PD-1 inhibitors. Severe adverse events (grade 3/4) were observed in 2 (15.4%) of the 13 patients in our cohort and 3 (13.0%) of the 23 patients in the total cohort. DISCUSSION In this study, we report the clinical characteristics of VVM and the treatment response to immune checkpoint inhibitors in a comprehensive cohort. Most women were diagnosed in advanced disease stages with poor prognostic indicators. Half of the nonmetastatic patients undergoing surgical lymph node assessment had lymph node metastases, and most our patients had a high mitotic count, both of which were recently shown to be important independent predictors for survival in women with VVMs.1,21 More than 80% of our cohort had disease recurrence or progression with a 2- and 5-year PFS rate of 35.4% and 23.2%, respectively. More than 50% of the women, who were free of distant metastases at diagnosis, developed metastatic disease. Therefore, women with VVM represent a high-risk group. Consistent with previous reports and unlike in cutaneous melanomas, only a small proportion of patients had BRAF mutations, limiting the treatment options with BRAF/MEK inhibitors.3,4 cKIT mutations were observed 14% and NRAS mutations in 13%; 2 patients were found to have a mutation in SF3B1, a mutation that was recently found to be more prevalent in VVMs and may be associated with worse outcome.22 The introduction of immune checkpoint inhibitors has led to an enormous progress in melanoma treatment and checkpoint inhibitors are now United States Food and Drug Administration and European Medicines Agency approved in the adjuvant and metastatic setting. The mechanism of action of CTLA-4 and PD-1 inhibitors is shown in Figure 1. For ipilimumab, we have observed an ORR of 8.3% and a CBR of 16.7% with median PFS of 3.0 months. The ORR is notably lower compared with 21.2% in cutaneous melanoma but identical to the recently reported response rate in mucosal melanomas combining data from 6 clinical trials (2 phase I trials: CA209-00323 and CA209-03824; 1 phase II trial: CheckMate 06925; and 3 phase III trials: CheckMate 066,26 CheckMate 037,27 and CheckMate 0678,10). FIGURE 1 Mechanism of action of immune checkpoint inhibitors in malignant melanoma of the vulva and vagina. Antigen presenting cells present the tumor antigen to T cells through MHC-II but also express inhibitory signals (CD80/86). CD80/86 binds to CTLA-4 and prevents T-cell activation. Ipilimumab, a monoclonal antibody that binds and inhibits CTLA-4, prevents this inhibition resulting in T-cell activation. Similarly, tumor cells express PD-L1 that binds to PD-1 receptors expressed on T cells, resulting in T-cell anergy. nivolumab and pembrolizumab (PD-1 inhibitors) bind PD-1 resulting in T-cell activation. APC, antigen presenting cells; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; MHC-I, major histocompatibility complex 1; MHC-II, major histocompatibility complex 2; PD-L1, programmed death-ligand 1; TCR, T-cell receptor. For PD-1 or a combination of PD-1 and CTLA-4 inhibitors, the ORR was 37.5% and the CBR was 62.5% with a median PFS of 9.0 months. This is again lower compared with the ORR of 60.4% reported for a combination of nivolumab and ipilimumab10 but comparable with 40.9% for nivolumab10 and 33.0% for pembrolizumab (combining 3 clinical trials, KEYNOTE-001,28 KEYNOTE-002,29 and KEYNOTE-0069,11 in cutaneous melanoma). Severe adverse events were observed in 15.4% of our cohort, which is comparable with the rate observed in mucosal melanomas.10 Strengths and Limitations This study investigates a large series of well-described cases of vulvar and vaginal melanoma diagnosed and treated at a comprehensive cancer center. We report clinical characteristics, outcome and treatment response with immune checkpoint inhibitors. The study is, however, limited by its retrospective design. Furthermore, including case reports into the analysis of treatment response adds the risk of publication bias. We have therefore analyzed our own series including all patients with VVM treated at our institution separately, and no distortion of the response rates was observed when adding the additional 10 cases previously published in the literature. CONCLUSIONS Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective with a complete or partial response being observed in approximately one third of women with locally unresectable or metastatic VVM. Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were associated with a significantly higher CBR and a trend toward longer progression-free survival compared with CTLA-4 inhibitors alone. The authors have declared they have no conflicts of interest. I.W.-W. is supported by a grant from the Austrian Science Fund (Project Number J 4382-B). The study was approved by the institutional review ethics board (UHN 19-5620). C.W. and I.W.-W. did the study conception, data acquisition and analysis, interpretation of data and original draft of the manuscript, review, and editing. S.L. did the investigation, methodology, review, and editing of the manuscript.	IPILIMUMAB, PEMBROLIZUMAB	DrugsGivenReaction	CC BY	33252450	18,648,560	2021-04-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune-mediated hyperthyroidism'.	Clinical Characteristics and Treatment Response With Checkpoint Inhibitors in Malignant Melanoma of the Vulva and Vagina. OBJECTIVE The aims of the study were to assess the clinical and histopathological characteristics of a comprehensive cohort of women with vulvovaginal melanoma (VVM) treated at our institution and to study the treatment response of checkpoint inhibitors in this patient cohort. METHODS This is a retrospective study of women with invasive VVM treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, over a period of 15 years. Clinical and histopathological characteristics, treatment, as well as treatment-related outcome were analyzed in 32 women. Treatment response was evaluated retrospectively using the "response criteria for use in trials testing immunotherapeutics" (iRECIST). The objective response rate was defined as the proportion of patients with complete or partial response based on the best overall response. RESULTS At a median follow-up of 37.8 months (5.8-110.4), 26 women (81.3%) had disease progression and 16 (50%) died. Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors. Ten additional cases were identified from previously published reports. The best objective response rate for immune checkpoint inhibitors was 30.4% (95% CI = 11.6%-49.2%) and the clinical benefit rate was 52.2% (95% CI = 31.8%-72.6%). The clinical benefit rate was significantly better for programmed cell death protein 1 inhibitors (or a combination) compared with ipilimumab alone (Fisher exact, p = .023). Grade 3/4 adverse events were observed in 3 (13.0%) of the 23 patients. CONCLUSIONS Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective in the treatment of metastatic melanoma in this patient cohort. Melanomas of the vulva and vagina account for 1% of all melanomas diagnosed in women and for 5.3% of all vulvar and 5.5% of all vaginal malignancies.1 Genital tract melanomas are commonly categorized as mucosal melanomas, but this has been questioned by studies showing different mutational characteristics suggesting that vulvovaginal melanomas (VVMs) may be classified as a unique subclass.2–5 Data on VVMs are scarce, and to date, only 1 prospective study has been completed: The Gynecologic Oncology Group 73 protocol suggested that the American Joint Committee on Cancer (AJCC) staging was the best predictor for survival and Breslow’s depth of invasion and lymphovascular space invasion were predictive of lymph node metastases.6 In a population-based study, we have recently shown that VVMs have a particularly poor prognosis with a median overall survival of 53 months in vulvar melanoma and 16 months in vaginal melanoma with no important change in survival over time.1 The treatment landscape of advanced and metastatic melanoma has drastically changed with the introduction of immune checkpoint inhibitors. Trials with the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor ipilimumab and the programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab have shown profound improvements of survival in patients with unresectable or metastatic melanoma.7–9 In a pooled analyses of clinical trials, mucosal melanomas, however, had lower response rates to nivolumab and pembrolizumab compared with cutaneous melanomas.10,11 Data for VVMs are scarce. The aims of this study are to describe clinical characteristics of a comprehensive cohort of women with VVM treated at our institution and to assess the treatment response of immune checkpoint inhibitors in this patient cohort. METHODS Study Population This is a retrospective single-center cohort study of women with invasive melanoma of the vulva or vagina treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada. The study protocol was approved by the institutional review ethics board (UHN 19-5620). All women with histologically confirmed invasive vulvar or vaginal melanoma diagnosed over a period of 15 years (2004–2018) were included and all cases were reviewed by an expert pathologist at the time of initial presentation; women with melanoma in situ without invasive components were not included. Vulvar melanomas were staged according to the AJCC staging classification in the eighth edition, and vaginal melanomas were classified as local, regional, or distant.12 Demographic data, Eastern Cooperative Oncology Group performance (ECOG) score, histopathology, type of surgery, lymph node assessment, adjuvant treatment, recurrence, treatment details for recurrent disease, and vital status were extracted from the electronic patient records. Programmed death-ligand 1 was not routinely tested in our patient cohort. Selection for immunotherapy was based on availability. Treatment response was evaluated retrospectively using the “response criteria for use in trials testing immunotherapeutics” (iRECIST).13 The objective response rate (ORR) was defined as the proportion of patients with complete (iCR) or partial response (iPR) based on the best overall response (iBOR).13 The clinical benefit rate (CBR) was defined as the proportion of patients with iCR, iPR, or stable disease (iSD). An iSD was assigned if no disease progression occurred for at least 2 months. Adverse events were categorized using the common terminology criteria for adverse events version 5.0.14 The treatment response of immune checkpoint inhibitors was analyzed in our cohort. In addition, treatment response from previously published case series and case reports was identified from PubMed using the search terms “ipilimumab,” “nivolumab,” or “pembrolizumab” in combination with “vulva” or “vagina,” and a separate analysis was performed for our cohort and the combined cohort. Reports without information on treatment response were not included. Statistical Analyses Descriptive statistics was used to report demographic data. Continuous variables were compared using the Student t test, Mann-Whitney test, or Wilcoxon test, as appropriate. Categorical data were compared using the Fisher exact test. Progression-free survival (PFS) and overall survival (OS) for the comprehensive cohort were calculated from the date of diagnosis to date of progression or death (PFS) and date of diagnosis to date of death (OS). Progression-free survival and OS for the subgroup analysis of immune checkpoint inhibitors were calculated from the date of treatment initiation to the date of progression or death, respectively. The Kaplan-Meier method with log-rank test was used to analyze PFS and OS. The 2- and 5-year survival rates were calculated using the Kaplan-Meier method. Statistical analysis was performed using SPSS Version 26, IBM, Armonk. A p value of less than .05 was considered statistically significant, all tests were 2-sided. Role of the Funding Source I.W.-W. is supported by a grant from the Austrian Science Fund (Project Number J 4382-B) to fund her fellowship at the Division of Dermatology, Department of Medicine, University of Toronto, Ontario, Canada. No external funding was used in the preparation of this manuscript. RESULTS Patient Characteristics In total, 32 women with invasive vulvar (n = 28) and vaginal (n = 4) melanoma were treated at our institution over a period of 15 years and included in our study. Demographic and clinical characteristics are shown in Table 1. The mean age at diagnosis was 66 years, and a significant proportion of patients was diagnosed with advanced disease stage, tumor thickness of greater than 4 mm, ulcerations, and high mitotic count; 31.3% already reported symptoms from melanoma including bleeding, pruritus, and pain at the time of diagnosis. Histologic characteristics are shown in Table 2. BRAF was tested in 25 patients and was positive in 2 (8.0%), cKIT was positive in 3 (13.6%) of the 22 patients tested, and NRAS mutations were detected in 2 (13.3%) of the 15 patients tested. A mutation in SF3B1 was found in 2 patients and 1 woman was found to have a PTEN mutation. TABLE 1 Patient Characteristics Parameter Age at diagnosis, y Mean ± SD 66.3 ± 14.0 Median (range) 66.0 (40–96) Pregnancy history Gravida 2 (0–3) Para 2 (0–3) ECOG performance status at diagnosis ECOG 0 23 (71.9%) ECOG 1 6 (18.8%) ECOG 2 2 (6.3%) ECOG 3 1 (3.1%) History of previous malignancy History of melanoma 2 (6.3%) History of other malignancy 7 (21.9%) Tumor stage at diagnosis Vulvar melanoma (n = 28) AJCC stage I 1 (3.6%) AJCC stage II 13 (46.4%) AJCC stage III 11 (39.3%) AJCC stage IV 3 (10.7%) Vaginal melanoma (n = 4) local 0 (0%) regional 4 (100%) distant 0 (0%) Reported symptoms Any symptoms reported 10 (31.3%) Pruritus 4 (12.5%) Bleeding 8 (25.0%) Pain 4 (12.5%) Organ involvement Labia majora 22 (68.8%) Labia minora 15 (46.9%) Clitoris 10 (31.1%) Urethra 4 (12.5%) Anus 0 (0%) Surgery Radical local excision 31 (96.9%) Exenteration 1 (3.1%) Surgical lymph node assessment Performed 27 (84.4%) Nodal metastases 14 (51.9%) Negative lymph nodes 13 (48.1%) TABLE 2 Histologic Characteristics Characteristics Tumor thickness, mm Median (range) 8 (1.1–68) ≤1.00 0 (0%) 1.01–2.00 4 (12.9%) 2.01–4.00 7 (22.6%) >4.00 20 (62.5%) Ulceration Present 24 (77.4%) Absent 7 (21.9%) Mitotic count, mitoses/mm2 Median (range) 8 (0–50) 0 1 (3.4%) 1 1 (3.4%) 2–10 14 (48.3%) >10 13 (44.8%) All women underwent surgery, and the lymph node status was surgically evaluated in 84.4% of all patients and in 88.0% of those with nonmetastatic vulvar melanoma. Adjuvant systemic treatment was given in 5 patients (15.6%): adjuvant interferon α in 3 and nivolumab in 2 patients, and their outcome is reported hereinafter. Outcome At a median follow-up of 37.8 months (5.8–110.4), 26 (81.3%) women had disease progression and 16 (50%) died. The median PFS was 17.7 months (95% CI = 5.5–29.8 months), and the 2- and 5-year PFS rates were 35.4% and 23.2%, respectively. The median OS was 59.1 months (95% CI = 23.6–94.5 months), and the 2- and 5-year OS rates were 71.1% and 45.6%, respectively. The 2-year PFS rate by the AJCC stage in vulvar melanoma was as follows: stage I, 100%; stage II, 35.9%; stage III, 42.4%; stage IV, 33.3%; and in the 4 patients with regional vaginal melanoma, 0% (p = .126). Fifteen (51.7%) of the 29 nonmetastatic patients at diagnosis developed distant metastases with a median time to metastatic disease of 39.5 months (95% CI = 0–84.2 months). Two patients received adjuvant nivolumab: 1 patient with vaginal melanoma developed brain metastases during adjuvant treatment with nivolumab. She was treated with stereotactic radiation and switched to pembrolizumab. The best overall response was iSD, but she ultimately progressed and died of melanoma (see Table 3, PMH05). The second patient receiving adjuvant nivolumab had vulvar melanoma AJCC stage IIIC. She had a local recurrence after 77 months, which was excised, and she has now been recurrence-free for 8 months. TABLE 3 Characteristics of Women With Malignant Melanoma of the Vulva or Vagina Receiving Immune Checkpoint Inhibitors (Combining Our Own Patient Cohort and Patients Identified From the Literature) Patient Site Stage at treatment initiationa (metastases) Prior systemic therapy Prior XRT, Site Immunotherapy iBOR PFSb irAEs OSc Vital status PMH01 Vulva IIIC, unresectable None None Pembrolizumab iCPD 2 None 18 Alive with disease PMH02 Vulva IV (lung) None None Ipilimumab + nivolumab iSD 18 Uveitis G1, peripheral sensory neuropathy G3 18 Alive with disease PMH03 Vulva IV (liver) None None Ipilimumab + nivolumab iCPD 1 None 1 Died of disease PMH04 Vulva IV (liver) None None Nivolumab iPR 15 Hepatitis G1 15 Alive with disease PMH05 Vagina Distant (brain) Nivolumab, adjuvant None Pembrolizumab iSD 4 None 16 Died of disease PMH06 Vulva IV (lung) None None Ipilimumab iCR 56 None 56 Alive with NED PMH07 Vulva IV (lung, liver) Interferon, adjuvant None 1. Ipilimumab iCPD 3 Maculopapular exanthema G1, Hepatitis G1 17 Died of disease 2. Pembrolizumab iSD 4 None PMH08 Vulva IV (liver) None Liver 1. Ipilimumab iCPD 3 Maculopapular exanthema G1 50 Alive with disease 2. Pembrolizumab iPR 9 None PMH09 Vulva IV (lung, brain) Carboplatin/paclitaxel Brain Ipilimumab iCPD 3 None 6 Died of disease PMH10 Vulva IV (lung) Dacarbazine Groin 1. Ipilimumab iCPD 3 None 87 Alive with NED 2. Pembrolizumab iCR 77 Hyperthyroidism G2, DM G3, Erythema nodosum G1 PMH11 Vulva IV (lung, bone) None Vulva + groin Ipilimumab iCPD 1 None 1 Died of disease PMH12 Vulva IV (lung, abdomen) Carboplatin/paclitaxel Vulva + groin 1. Ipilimumab iCPD 3 None 16 Died of disease 2. Pembrolizumab iCPD 3 None PMH13 Vulva IV (lung, abdomen, soft tissue) Carboplatin/paclitaxel Abdomen + groin Ipilimumab iSD 2 None 13 Died of disease Indini115 Vulva IV (lung) CVD None Ipilimumab iCPD 4 None 7 Died of disease Indini215 Vulva IV (lung, bone) None None Pembrolizumab iPR 10 Arthralgia G2, hypothyroidism G2 10 Alive with disease Indini315 Vagina Distant (liver) None None Pembrolizumab iCPD 2 None 4 Alive with disease Indini415 Vagina Distant (n.s.) None Vagina Nivolumab iSD 4 Cutaneous rash G1 4 Alive with disease Indini515 Vagina Distant (liver, pancreas, soft tissues, bone) None None Ipilimumab iCPD 3 None 7 Died of disease Indini615 Vagina Distant (lung) Dacarbazine None Ipilimumab iCPD 3 None 18 Died of disease Daix116 Vagina Regional, unresectable None None Nivolumab iCR 8 Pruritus G1 8 Alive with NED Anko117 Vagina Distant (liver, lung, bone) None None Nivolumab iPR/iCR 17 Thyroiditis, n.s. 17 Alive Komatsu-Fujii118 Vagina Distant (lung) None None 1. Nivolumab iCPD n.s. n.s. n.s. Alive with disease 2. Pembrolizumab iCPD n.s. n.s. 3. Ipilimumab iCPD n.s. n.s. Inoue119 Vagina Distant (brain) None Brain Nivolumab iCPD 2 Hepatitis G3 n.s. Alive with disease Characteristics of the 13 patients treated our institution (PMH1–PMH13) and 10 additional previously published cases. aStage at initiation of treatment with immune checkpoint inhibitor, AJCC stage for vulvar melanomas and local/regional/distant for vaginal melanomas. bPFS in months defined from treatment initiation with immune checkpoint inhibitor to date of progression or death. cOS in months defined from treatment initiation with first immune checkpoint inhibitor to date of last follow-up or death. CVD indicates cisplatin-vinblastine-dacarbazine; DM, diabetes mellitus; G, grade; iCPD, confirmed progressive disease; irAEs, immune-related adverse events; NED, no evidence of disease; n.s., not specified; XRT, radiation therapy. Treatment Response of Immune Checkpoint Inhibitors in Unresectable or Metastatic Melanoma Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors, and 4 patients were initially treated with ipilimumab and switched to a PD-1 inhibitor after treatment failure. The best overall ORR with immunotherapy in the 13 patients was 30.8% (95% CI = 5.7%–55.9%), and the CBR was 61.5% (95% CI = 35.1%–88.0%). The median PFS was 4.0 months (95% CI = 2.3–5.7 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). Ipilimumab was given in 8 patients; the ORR was 12.5% (95% CI = 0%–35.4%), and the CBR was 25.0% (95% CI = 0%–55.0%). Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were given in 9 patients; the ORR was 33.3% (95% CI = 2.5%–64.1%), and the CBR was 66.7% (95% CI = 35.9%–97.5%). In addition, 13 patients with VVM receiving immune checkpoint inhibitors were identified from previously published cases in the literature15–20; 10 patients with metastatic or unresectable VVM were included (see Table 3); 3 patients, who received neoadjuvant ipilimumab and radiation and subsequently underwent surgery, were not included.20 The best overall ORR with immune checkpoint inhibitors in the combined cohort of the 23 patients was 30.4% (95% CI = 11.6%–49.2%), and the CBR was 52.2% (95% CI = 31.8%–72.6%). The median PFS was 4.0 months (95% CI = 2.7–5.3 months), and the median OS was 17.0 months (95% CI = 12.7–21.3 months). The ORR for ipilimumab alone was 8.3% (95% CI = 0%–24%) compared with 37.5% (95% CI = 13.8%–61.2%, Fisher exact, p = .184) for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The CBR was 16.7% (95% CI = 0%–37.8%) for ipilimumab compared with 62.5% (95% CI = 38.8%–86.2%, Fisher exact, p = .023) for PD-1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors. The median PFS for ipilimumab alone was 3.0 months (95% CI = 2.6–3.4 months) compared with 9.0 months (95% CI = 1.9–16.1 months, p = .062) for PD-1 inhibitors or the combination of CTLA-4 and PD-1 inhibitors. Severe adverse events (grade 3/4) were observed in 2 (15.4%) of the 13 patients in our cohort and 3 (13.0%) of the 23 patients in the total cohort. DISCUSSION In this study, we report the clinical characteristics of VVM and the treatment response to immune checkpoint inhibitors in a comprehensive cohort. Most women were diagnosed in advanced disease stages with poor prognostic indicators. Half of the nonmetastatic patients undergoing surgical lymph node assessment had lymph node metastases, and most our patients had a high mitotic count, both of which were recently shown to be important independent predictors for survival in women with VVMs.1,21 More than 80% of our cohort had disease recurrence or progression with a 2- and 5-year PFS rate of 35.4% and 23.2%, respectively. More than 50% of the women, who were free of distant metastases at diagnosis, developed metastatic disease. Therefore, women with VVM represent a high-risk group. Consistent with previous reports and unlike in cutaneous melanomas, only a small proportion of patients had BRAF mutations, limiting the treatment options with BRAF/MEK inhibitors.3,4 cKIT mutations were observed 14% and NRAS mutations in 13%; 2 patients were found to have a mutation in SF3B1, a mutation that was recently found to be more prevalent in VVMs and may be associated with worse outcome.22 The introduction of immune checkpoint inhibitors has led to an enormous progress in melanoma treatment and checkpoint inhibitors are now United States Food and Drug Administration and European Medicines Agency approved in the adjuvant and metastatic setting. The mechanism of action of CTLA-4 and PD-1 inhibitors is shown in Figure 1. For ipilimumab, we have observed an ORR of 8.3% and a CBR of 16.7% with median PFS of 3.0 months. The ORR is notably lower compared with 21.2% in cutaneous melanoma but identical to the recently reported response rate in mucosal melanomas combining data from 6 clinical trials (2 phase I trials: CA209-00323 and CA209-03824; 1 phase II trial: CheckMate 06925; and 3 phase III trials: CheckMate 066,26 CheckMate 037,27 and CheckMate 0678,10). FIGURE 1 Mechanism of action of immune checkpoint inhibitors in malignant melanoma of the vulva and vagina. Antigen presenting cells present the tumor antigen to T cells through MHC-II but also express inhibitory signals (CD80/86). CD80/86 binds to CTLA-4 and prevents T-cell activation. Ipilimumab, a monoclonal antibody that binds and inhibits CTLA-4, prevents this inhibition resulting in T-cell activation. Similarly, tumor cells express PD-L1 that binds to PD-1 receptors expressed on T cells, resulting in T-cell anergy. nivolumab and pembrolizumab (PD-1 inhibitors) bind PD-1 resulting in T-cell activation. APC, antigen presenting cells; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; MHC-I, major histocompatibility complex 1; MHC-II, major histocompatibility complex 2; PD-L1, programmed death-ligand 1; TCR, T-cell receptor. For PD-1 or a combination of PD-1 and CTLA-4 inhibitors, the ORR was 37.5% and the CBR was 62.5% with a median PFS of 9.0 months. This is again lower compared with the ORR of 60.4% reported for a combination of nivolumab and ipilimumab10 but comparable with 40.9% for nivolumab10 and 33.0% for pembrolizumab (combining 3 clinical trials, KEYNOTE-001,28 KEYNOTE-002,29 and KEYNOTE-0069,11 in cutaneous melanoma). Severe adverse events were observed in 15.4% of our cohort, which is comparable with the rate observed in mucosal melanomas.10 Strengths and Limitations This study investigates a large series of well-described cases of vulvar and vaginal melanoma diagnosed and treated at a comprehensive cancer center. We report clinical characteristics, outcome and treatment response with immune checkpoint inhibitors. The study is, however, limited by its retrospective design. Furthermore, including case reports into the analysis of treatment response adds the risk of publication bias. We have therefore analyzed our own series including all patients with VVM treated at our institution separately, and no distortion of the response rates was observed when adding the additional 10 cases previously published in the literature. CONCLUSIONS Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective with a complete or partial response being observed in approximately one third of women with locally unresectable or metastatic VVM. Programmed cell death protein 1 inhibitors or a combination of CTLA-4 and PD-1 inhibitors were associated with a significantly higher CBR and a trend toward longer progression-free survival compared with CTLA-4 inhibitors alone. The authors have declared they have no conflicts of interest. I.W.-W. is supported by a grant from the Austrian Science Fund (Project Number J 4382-B). The study was approved by the institutional review ethics board (UHN 19-5620). C.W. and I.W.-W. did the study conception, data acquisition and analysis, interpretation of data and original draft of the manuscript, review, and editing. S.L. did the investigation, methodology, review, and editing of the manuscript.	IPILIMUMAB, PEMBROLIZUMAB	DrugsGivenReaction	CC BY	33252450	18,648,560	2021-04-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'.	Fatal Case of Chronic Jamestown Canyon Virus Encephalitis Diagnosed by Metagenomic Sequencing in Patient Receiving Rituximab. A 56-year-old man receiving rituximab who had months of neurologic symptoms was found to have Jamestown Canyon virus in cerebrospinal fluid by clinical metagenomic sequencing. The patient died, and postmortem examination revealed extensive neuropathologic abnormalities. Deep sequencing enabled detailed characterization of viral genomes from the cerebrospinal fluid, cerebellum, and cerebral cortex. Jamestown Canyon orthobunyavirus (JCV) is a negative-sense RNA virus in the California serogroup. Its tripartite genome comprises small (nucleocapsid), medium (glycoprotein), and large (polymerase) segments. JCV is distributed throughout the United States and Canada and has been isolated from multiple mammals and mosquitoes (1,2). Most infections occur in adults, during the summer, and are asymptomatic, but manifestations can include fever and acute meningoencephalitis (2). Cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis with elevated protein and normal glucose. Diagnosis is made by detection of JCV IgM in serum or CSF and confirmed by plaque-reduction neutralization testing to rule out cross-reactivity with other California serogroup viruses (3). Detection of viral RNA in human CSF has rarely been described, with viremia presumed to be of short duration, so reverse transcription PCR (RT-PCR) is not routinely used for diagnosis (3–5). No specific treatments are available, although intravenous ribavirin has been reported to improve seizures (6). Because of the limited number of cases described, the full range of findings associated with JCV infection is unknown. No fatal cases were reported to the Centers for Disease Control and Prevention (CDC) before 2017, and no autopsy reports have been published (7). The Case-Patient A 56-year-old man from New England with a history of mantle cell lymphoma in remission, receiving maintenance rituximab since 2014, had fatigue, arthralgias, and weight loss in summer 2017. He was empirically treated for Lyme disease without improvement, had progressive insomnia and inattention, and was eventually admitted for workup of rapidly progressive dementia in April 2018. On examination, he had impaired arousal and attention (Montreal Cognitive Assessment score 6 of 30). Cranial nerve, tone, strength, sensory, and reflex examinations were normal. Gait was wide-based and slow without ataxia or parkinsonism. Magnetic resonance imaging of the brain showed mild ventriculomegaly attributed to atrophy but was otherwise unremarkable, without contrast enhancement, cortical diffusion restriction, mass lesions, hemorrhage, or infarction (Figure 1). Electroencephalography showed moderate bihemispheric slowing without epileptiform features. CSF from multiple lumbar punctures showed mild lymphocytic pleocytosis (0–22 leukocytes/μL, 83%–98% lymphocytes), elevated total protein (40–116 mg/dL; reference 10–44 mg/dL), and unremarkable glucose (65–78 mg/dL; reference 40–80 mg/dL) (Appendix Table 1). An extensive infectious, autoimmune, and neurodegenerative disease workup was normal (Appendix Table 2). Figure 1 Brain imaging and autopsy findings in a case of chronic Jamestown Canyon virus (JCV) meningoencephalitis in a patient receiving rituximab, Boston, Massachusetts, USA. A) Brain magnetic resonance imaging T2-weighted fluid-attenuated inversion recovery showed mild atrophy with secondary ventriculomegaly but was otherwise unremarkable. B) Brain positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography showed global hypometabolism. Color scale ranges from blue-green (hypometabolic) to orange-white (hypermetabolic). C, D) Hematoxylin and eosin stained section of cerebral cortex at low magnification shows loss of neurons and perivascular chronic inflammation (C), compared with a JCV-negative control with a normal complement of cortical neurons (D). E, F) Higher-power magnification of cerebral cortex (E) and hippocampus (F) show microgliosis, microglial nodules, and neuronophagia (arrow). G, H) Severe Purkinje cell loss, Bergmann gliois (arrows), and microgliosis (arrowheads) of the molecular layer are present in the cerebellum (G), compared with a JCV-negative control with normal complement of Purkinje cells (H). I, J) Immunohistochemistry shows abundant perivascular, parenchymal, and leptomeningeal CD3+ T cells (I) and is negative for B-cell lineage–specific activator protein positive B cells (J). Panels C, D, I, and J, original magnification ×100; panels E, F, G, and H, original magnification ×200. A CSF sample collected in April 2018 underwent clinical metagenomic next-generation sequencing (mNGS) testing at the University of California–San Francisco (8) and was positive for California encephalitis virus most closely matching JCV, with reads mapping to 2 of the 3 viral genome segments (Appendix Figure 1). Another CSF sample, obtained approximately 3 weeks later in May, was negative for JCV by RT-PCR performed by CDC’s Arboviral Diseases Branch (Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases; Fort Collins, CO, USA); however, concurrent serum JCV RT-PCR was positive. Results of JCV IgM and neutralizing antibody testing were negative for CSF and blood from the samples obtained in May. Concurrent samples had 0% CD20+ circulating lymphocytes (reference 3%–20% lymphocytes), attributed to rituximab treatment, last administered in December 2017. The patient was treated with intravenous immunoglobulin (total 2 g/kg), followed by a 2-week course of favipiravir, an experimental inhibitor of viral RNA polymerase, without improvement. His mental status deteriorated to a comatose state. He was transitioned to comfort care and died in June 2018, ≈1 year after suspected symptom onset. At autopsy, the unfixed brain weighed 1,240 g and appeared grossly normal, with no masses, hemorrhage, infarctions, or herniation. Histologic abnormalities were most prominent in the cerebral cortex (particularly frontal and temporal lobes), cerebellum, and hippocampus; milder changes in basal ganglia, thalamus, and brainstem were observed, including severe loss of neurons, diffuse microgliosis with microglial nodules and neuronophagia, and perivascular and parenchymal chronic inflammation (Figure 1). Leptomeninges showed numerous chronic inflammatory cells. No viral inclusions were identified. There was no evidence of lymphoma. Immunohistochemical staining highlighted abundant perivascular, parenchymal, and leptomeningeal T cells with a complete lack of B cells. Formalin-fixed paraffin-embedded brain tissue was positive for JCV by RT-PCR (performed by CDC’s Arboviral Diagnostic and Reference Laboratory); results were negative for immunohistochemistry for flaviviruses and enteroviruses (performed by CDC’s Infectious Diseases Pathology Branch [Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Atlanta, GA, USA]). Complete or near-complete JCV genomes were recovered from premortem CSF and postmortem cerebellum and cortex tissue (both frozen and formalin-fixed paraffin-embedded) (Table; Appendix Supplementary Methods, Figure 2). Phylogenetic analysis of the small (nucleocapsid) segment showed that sequences from this patient were most closely related to JCV from mosquitoes in Connecticut (Figure 2, panel A) (9). Comparison of JCV genomes between this patient’s CSF, cerebellum, and cortex revealed 27 high-confidence within-patient single-nucleotide polymorphisms (SNPs) (Figure 2, panel B; Appendix Tables 3, 4). For 13 SNPs, the variant present in CSF was different from that in cerebellum and cortex, suggesting evolution over time. For another 4 SNPs, the variant present in cerebellum was different from that in cortex, suggesting compartmentalization. The remaining 10 SNPs could represent either compartmentalization or evolution over time, because only 1 brain tissue (cerebellum or cortex) was sequenced to sufficient depth. Variability was greater in the small segment (nucleocapsid) and medium segment (glycoprotein) than the large segment (polymerase). Table Results of JCV sequencing across samples from an immunocompromised patient with encephalitis, Boston, Massachusetts, USA* Specimen Method Total reads† Unique JCV reads‡ % Genome assembled, by segment§ Mean depth, by genome segment§ Small Medium Large Small Medium Large CSF mNGS, MSSPE 1,917,836,676 894 100 80 90 14.3 3.7 5.3 Cerebellum, frozen mNGS, MSSPE 1,031,252,808 558 98 66 100 9.4 1.3 6.1 Cerebellum, FFPE mNGS, hybrid capture 38,974,996 294 70 56 90 7.1 1.2 3.1 Cortex, frozen mNGS, MSSPE 729,867,496 3,652 100 100 100 61.6 15.2 40.2 Cortex, FFPE mNGS, hybrid capture 101,331,284 518 100 72 91 20.1 2.1 4.5 *Methods detailed in Appendix. CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; mNGS, metagenomic next-generation sequencing; MSSPE, metagenomic sequencing with spiked primer enrichment. †Total reads reflect the number of raw reads that were generated from each sample. ‡Unique JCV reads reflects removal of PCR duplicates and mapping to JCV reference sequences. §Small, 989 nt; Medium, 4,509 nt; Large, 6,960 nt. Figure 2 JCV genome analyses in a case of chronic JCV meningoencephalitis in a patient on rituximab, Boston, Massachusetts, USA. A) Maximum-likelihood phylogenetic tree of the coding region of the JCV small segment (nucleocapsid). Sequences from the patient (bold) were most closely related to a JCV strain isolated from Simsbury, Connecticut, USA (GenBank accession no. EF681842), with ≈70% bootstrap support. Clades A, B1, and B2 are as previously reported (9). B) Single-nucleotide polymorphisms (SNPs) observed between samples from patient in this study. The consensus genome derived from each sample was aligned to a mosquito-derived JCV sequence (GenBank accession nos. HM007356 [S segment], HM007357 [M segment], and HM007358 [L segment], all represented in the figure as HM00735X). For each sample in this study, the light gray bar indicates positions for which there was coverage of >3 reads. Using the sequence derived from CSF as the reference, positions with a SNP are marked with a star; black indicates a synonymous change, and red indicates a nonsynonymous change. Only high-confidence (confirmed) SNPs are shown in this figure; all SNPs observed are shown in Appendix Tables 3, 4. Sequence data is available under National Center for Biotechnology Information BioProject no. PRJNA662969 (GenBank accession nos. MW072986–MW073000). CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; L, large; M, medium; S, small. Conclusions We describe an unusual fatal case of chronic JCV encephalitis in a patient who was being treated with rituximab. In contrast to this case, previously described patients with JCV have had acute illness, and JCV infection is rarely fatal (7,10). The neuropathologic findings in this patient, although nonspecific, are similar to those of a cerebellar biopsy from a patient with JCV encephalitis that showed severe loss of Purkinje and granule cells, diffuse microgliosis of the molecular layer, and leptomeningeal inflammation (5). The lack of distinguishing clinical, radiographic, and pathologic features of JCV underscores the diagnostic utility of clinical mNGS (8). Attributable in part to low incidence and lack of commercially available targeted testing, JCV is often not considered a priori, especially in the setting of chronic progressive neurologic illness. As a further complication, standard clinical testing by serology can be negative in the setting of B-cell–depleting therapy; our patient had negative JCV serologic tests and lack of B lymphocytes by immunohistochemical staining. Similar phenomena have been reported in rituximab-treated patients with other arboviral infections (e.g., Cache Valley orthobunyavirus, Powassan virus, and West Nile virus) who lack detectable antibodies but remain viremic longer than immunocompetent patients, highlighting the importance of nucleic acid–based testing methods (11–13). In addition to diagnosis, mNGS also provides valuable information about pathogen genomics. We report the unique assembly of a JCV genome from human clinical samples, an important advance in the study of JVC pathogenesis, virus evolution, and differences between the enzootic transmission cycle and human infection (14). The functional importance of the identified SNPs could not be evaluated from the genomic data alone; however, none were associated with alterations of potential N-linked glycosylation sites, cysteine bonds, or the conserved fusion domain (15). One SNP that arose between CSF and brain (small segment gA397G; aT109A) also varied between JCV strains with different neurovirulence in mice, although the functional importance is unknown (4). Although treatment options for JCV infection are largely unexplored, response to antiviral drugs probably depends on initiating treatment early in the disease course and reaching therapeutic levels in the CSF before extensive neuronal loss. Thus, broad-spectrum molecular assays such as mNGS could potentially lead to earlier treatment with improved outcomes (8). Appendix Additional information about a fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Acknowledgments We thank the patient’s family for granting permission to publish this information. We also wish to acknowledge contributions by Asmeeta Achari, Sarah Reagan-Steiner, and the molecular pathology and immunohistochemistry teams at CDC’s Infectious Disease Pathology Branch. This study was supported by the National Institutes of Health (grant no. U19AI110818 awarded to P.C.S, grant no. KL2 TR001100 awarded to A.P., and grant no. R33AI129455 awarded to C.Y.C.), the Charles and Helen Schwab Foundation (grant awarded to C.Y.C.), and a Broadnext10 gift from the Broad Institute (awarded to P.C.S.). Dr. Solomon is a neuropathologist at Brigham and Women’s Hospital and Harvard Medical School, in Boston, Massachusetts. His primary research interests include viral infections of the central nervous system. Suggested citation for this article: Solomon IH, Ganesh VS, Yu G, Deng XD, Wilson MR, Miller S, et al. Fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203448 1 These authors contributed equally to this article. 2 These senior authors contributed equally to this article. 3 Current affiliation: Emory University, Atlanta, Georgia, USA.	FAVIPIRAVIR, HUMAN IMMUNOGLOBULIN G, RITUXIMAB	DrugsGivenReaction	CC BY	33261720	19,026,565	2021-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.	Fatal Case of Chronic Jamestown Canyon Virus Encephalitis Diagnosed by Metagenomic Sequencing in Patient Receiving Rituximab. A 56-year-old man receiving rituximab who had months of neurologic symptoms was found to have Jamestown Canyon virus in cerebrospinal fluid by clinical metagenomic sequencing. The patient died, and postmortem examination revealed extensive neuropathologic abnormalities. Deep sequencing enabled detailed characterization of viral genomes from the cerebrospinal fluid, cerebellum, and cerebral cortex. Jamestown Canyon orthobunyavirus (JCV) is a negative-sense RNA virus in the California serogroup. Its tripartite genome comprises small (nucleocapsid), medium (glycoprotein), and large (polymerase) segments. JCV is distributed throughout the United States and Canada and has been isolated from multiple mammals and mosquitoes (1,2). Most infections occur in adults, during the summer, and are asymptomatic, but manifestations can include fever and acute meningoencephalitis (2). Cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis with elevated protein and normal glucose. Diagnosis is made by detection of JCV IgM in serum or CSF and confirmed by plaque-reduction neutralization testing to rule out cross-reactivity with other California serogroup viruses (3). Detection of viral RNA in human CSF has rarely been described, with viremia presumed to be of short duration, so reverse transcription PCR (RT-PCR) is not routinely used for diagnosis (3–5). No specific treatments are available, although intravenous ribavirin has been reported to improve seizures (6). Because of the limited number of cases described, the full range of findings associated with JCV infection is unknown. No fatal cases were reported to the Centers for Disease Control and Prevention (CDC) before 2017, and no autopsy reports have been published (7). The Case-Patient A 56-year-old man from New England with a history of mantle cell lymphoma in remission, receiving maintenance rituximab since 2014, had fatigue, arthralgias, and weight loss in summer 2017. He was empirically treated for Lyme disease without improvement, had progressive insomnia and inattention, and was eventually admitted for workup of rapidly progressive dementia in April 2018. On examination, he had impaired arousal and attention (Montreal Cognitive Assessment score 6 of 30). Cranial nerve, tone, strength, sensory, and reflex examinations were normal. Gait was wide-based and slow without ataxia or parkinsonism. Magnetic resonance imaging of the brain showed mild ventriculomegaly attributed to atrophy but was otherwise unremarkable, without contrast enhancement, cortical diffusion restriction, mass lesions, hemorrhage, or infarction (Figure 1). Electroencephalography showed moderate bihemispheric slowing without epileptiform features. CSF from multiple lumbar punctures showed mild lymphocytic pleocytosis (0–22 leukocytes/μL, 83%–98% lymphocytes), elevated total protein (40–116 mg/dL; reference 10–44 mg/dL), and unremarkable glucose (65–78 mg/dL; reference 40–80 mg/dL) (Appendix Table 1). An extensive infectious, autoimmune, and neurodegenerative disease workup was normal (Appendix Table 2). Figure 1 Brain imaging and autopsy findings in a case of chronic Jamestown Canyon virus (JCV) meningoencephalitis in a patient receiving rituximab, Boston, Massachusetts, USA. A) Brain magnetic resonance imaging T2-weighted fluid-attenuated inversion recovery showed mild atrophy with secondary ventriculomegaly but was otherwise unremarkable. B) Brain positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography showed global hypometabolism. Color scale ranges from blue-green (hypometabolic) to orange-white (hypermetabolic). C, D) Hematoxylin and eosin stained section of cerebral cortex at low magnification shows loss of neurons and perivascular chronic inflammation (C), compared with a JCV-negative control with a normal complement of cortical neurons (D). E, F) Higher-power magnification of cerebral cortex (E) and hippocampus (F) show microgliosis, microglial nodules, and neuronophagia (arrow). G, H) Severe Purkinje cell loss, Bergmann gliois (arrows), and microgliosis (arrowheads) of the molecular layer are present in the cerebellum (G), compared with a JCV-negative control with normal complement of Purkinje cells (H). I, J) Immunohistochemistry shows abundant perivascular, parenchymal, and leptomeningeal CD3+ T cells (I) and is negative for B-cell lineage–specific activator protein positive B cells (J). Panels C, D, I, and J, original magnification ×100; panels E, F, G, and H, original magnification ×200. A CSF sample collected in April 2018 underwent clinical metagenomic next-generation sequencing (mNGS) testing at the University of California–San Francisco (8) and was positive for California encephalitis virus most closely matching JCV, with reads mapping to 2 of the 3 viral genome segments (Appendix Figure 1). Another CSF sample, obtained approximately 3 weeks later in May, was negative for JCV by RT-PCR performed by CDC’s Arboviral Diseases Branch (Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases; Fort Collins, CO, USA); however, concurrent serum JCV RT-PCR was positive. Results of JCV IgM and neutralizing antibody testing were negative for CSF and blood from the samples obtained in May. Concurrent samples had 0% CD20+ circulating lymphocytes (reference 3%–20% lymphocytes), attributed to rituximab treatment, last administered in December 2017. The patient was treated with intravenous immunoglobulin (total 2 g/kg), followed by a 2-week course of favipiravir, an experimental inhibitor of viral RNA polymerase, without improvement. His mental status deteriorated to a comatose state. He was transitioned to comfort care and died in June 2018, ≈1 year after suspected symptom onset. At autopsy, the unfixed brain weighed 1,240 g and appeared grossly normal, with no masses, hemorrhage, infarctions, or herniation. Histologic abnormalities were most prominent in the cerebral cortex (particularly frontal and temporal lobes), cerebellum, and hippocampus; milder changes in basal ganglia, thalamus, and brainstem were observed, including severe loss of neurons, diffuse microgliosis with microglial nodules and neuronophagia, and perivascular and parenchymal chronic inflammation (Figure 1). Leptomeninges showed numerous chronic inflammatory cells. No viral inclusions were identified. There was no evidence of lymphoma. Immunohistochemical staining highlighted abundant perivascular, parenchymal, and leptomeningeal T cells with a complete lack of B cells. Formalin-fixed paraffin-embedded brain tissue was positive for JCV by RT-PCR (performed by CDC’s Arboviral Diagnostic and Reference Laboratory); results were negative for immunohistochemistry for flaviviruses and enteroviruses (performed by CDC’s Infectious Diseases Pathology Branch [Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Atlanta, GA, USA]). Complete or near-complete JCV genomes were recovered from premortem CSF and postmortem cerebellum and cortex tissue (both frozen and formalin-fixed paraffin-embedded) (Table; Appendix Supplementary Methods, Figure 2). Phylogenetic analysis of the small (nucleocapsid) segment showed that sequences from this patient were most closely related to JCV from mosquitoes in Connecticut (Figure 2, panel A) (9). Comparison of JCV genomes between this patient’s CSF, cerebellum, and cortex revealed 27 high-confidence within-patient single-nucleotide polymorphisms (SNPs) (Figure 2, panel B; Appendix Tables 3, 4). For 13 SNPs, the variant present in CSF was different from that in cerebellum and cortex, suggesting evolution over time. For another 4 SNPs, the variant present in cerebellum was different from that in cortex, suggesting compartmentalization. The remaining 10 SNPs could represent either compartmentalization or evolution over time, because only 1 brain tissue (cerebellum or cortex) was sequenced to sufficient depth. Variability was greater in the small segment (nucleocapsid) and medium segment (glycoprotein) than the large segment (polymerase). Table Results of JCV sequencing across samples from an immunocompromised patient with encephalitis, Boston, Massachusetts, USA* Specimen Method Total reads† Unique JCV reads‡ % Genome assembled, by segment§ Mean depth, by genome segment§ Small Medium Large Small Medium Large CSF mNGS, MSSPE 1,917,836,676 894 100 80 90 14.3 3.7 5.3 Cerebellum, frozen mNGS, MSSPE 1,031,252,808 558 98 66 100 9.4 1.3 6.1 Cerebellum, FFPE mNGS, hybrid capture 38,974,996 294 70 56 90 7.1 1.2 3.1 Cortex, frozen mNGS, MSSPE 729,867,496 3,652 100 100 100 61.6 15.2 40.2 Cortex, FFPE mNGS, hybrid capture 101,331,284 518 100 72 91 20.1 2.1 4.5 *Methods detailed in Appendix. CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; mNGS, metagenomic next-generation sequencing; MSSPE, metagenomic sequencing with spiked primer enrichment. †Total reads reflect the number of raw reads that were generated from each sample. ‡Unique JCV reads reflects removal of PCR duplicates and mapping to JCV reference sequences. §Small, 989 nt; Medium, 4,509 nt; Large, 6,960 nt. Figure 2 JCV genome analyses in a case of chronic JCV meningoencephalitis in a patient on rituximab, Boston, Massachusetts, USA. A) Maximum-likelihood phylogenetic tree of the coding region of the JCV small segment (nucleocapsid). Sequences from the patient (bold) were most closely related to a JCV strain isolated from Simsbury, Connecticut, USA (GenBank accession no. EF681842), with ≈70% bootstrap support. Clades A, B1, and B2 are as previously reported (9). B) Single-nucleotide polymorphisms (SNPs) observed between samples from patient in this study. The consensus genome derived from each sample was aligned to a mosquito-derived JCV sequence (GenBank accession nos. HM007356 [S segment], HM007357 [M segment], and HM007358 [L segment], all represented in the figure as HM00735X). For each sample in this study, the light gray bar indicates positions for which there was coverage of >3 reads. Using the sequence derived from CSF as the reference, positions with a SNP are marked with a star; black indicates a synonymous change, and red indicates a nonsynonymous change. Only high-confidence (confirmed) SNPs are shown in this figure; all SNPs observed are shown in Appendix Tables 3, 4. Sequence data is available under National Center for Biotechnology Information BioProject no. PRJNA662969 (GenBank accession nos. MW072986–MW073000). CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; L, large; M, medium; S, small. Conclusions We describe an unusual fatal case of chronic JCV encephalitis in a patient who was being treated with rituximab. In contrast to this case, previously described patients with JCV have had acute illness, and JCV infection is rarely fatal (7,10). The neuropathologic findings in this patient, although nonspecific, are similar to those of a cerebellar biopsy from a patient with JCV encephalitis that showed severe loss of Purkinje and granule cells, diffuse microgliosis of the molecular layer, and leptomeningeal inflammation (5). The lack of distinguishing clinical, radiographic, and pathologic features of JCV underscores the diagnostic utility of clinical mNGS (8). Attributable in part to low incidence and lack of commercially available targeted testing, JCV is often not considered a priori, especially in the setting of chronic progressive neurologic illness. As a further complication, standard clinical testing by serology can be negative in the setting of B-cell–depleting therapy; our patient had negative JCV serologic tests and lack of B lymphocytes by immunohistochemical staining. Similar phenomena have been reported in rituximab-treated patients with other arboviral infections (e.g., Cache Valley orthobunyavirus, Powassan virus, and West Nile virus) who lack detectable antibodies but remain viremic longer than immunocompetent patients, highlighting the importance of nucleic acid–based testing methods (11–13). In addition to diagnosis, mNGS also provides valuable information about pathogen genomics. We report the unique assembly of a JCV genome from human clinical samples, an important advance in the study of JVC pathogenesis, virus evolution, and differences between the enzootic transmission cycle and human infection (14). The functional importance of the identified SNPs could not be evaluated from the genomic data alone; however, none were associated with alterations of potential N-linked glycosylation sites, cysteine bonds, or the conserved fusion domain (15). One SNP that arose between CSF and brain (small segment gA397G; aT109A) also varied between JCV strains with different neurovirulence in mice, although the functional importance is unknown (4). Although treatment options for JCV infection are largely unexplored, response to antiviral drugs probably depends on initiating treatment early in the disease course and reaching therapeutic levels in the CSF before extensive neuronal loss. Thus, broad-spectrum molecular assays such as mNGS could potentially lead to earlier treatment with improved outcomes (8). Appendix Additional information about a fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Acknowledgments We thank the patient’s family for granting permission to publish this information. We also wish to acknowledge contributions by Asmeeta Achari, Sarah Reagan-Steiner, and the molecular pathology and immunohistochemistry teams at CDC’s Infectious Disease Pathology Branch. This study was supported by the National Institutes of Health (grant no. U19AI110818 awarded to P.C.S, grant no. KL2 TR001100 awarded to A.P., and grant no. R33AI129455 awarded to C.Y.C.), the Charles and Helen Schwab Foundation (grant awarded to C.Y.C.), and a Broadnext10 gift from the Broad Institute (awarded to P.C.S.). Dr. Solomon is a neuropathologist at Brigham and Women’s Hospital and Harvard Medical School, in Boston, Massachusetts. His primary research interests include viral infections of the central nervous system. Suggested citation for this article: Solomon IH, Ganesh VS, Yu G, Deng XD, Wilson MR, Miller S, et al. Fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203448 1 These authors contributed equally to this article. 2 These senior authors contributed equally to this article. 3 Current affiliation: Emory University, Atlanta, Georgia, USA.	FAVIPIRAVIR, HUMAN IMMUNOGLOBULIN G, RITUXIMAB	DrugsGivenReaction	CC BY	33261720	19,026,565	2021-01
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'?	Fatal Case of Chronic Jamestown Canyon Virus Encephalitis Diagnosed by Metagenomic Sequencing in Patient Receiving Rituximab. A 56-year-old man receiving rituximab who had months of neurologic symptoms was found to have Jamestown Canyon virus in cerebrospinal fluid by clinical metagenomic sequencing. The patient died, and postmortem examination revealed extensive neuropathologic abnormalities. Deep sequencing enabled detailed characterization of viral genomes from the cerebrospinal fluid, cerebellum, and cerebral cortex. Jamestown Canyon orthobunyavirus (JCV) is a negative-sense RNA virus in the California serogroup. Its tripartite genome comprises small (nucleocapsid), medium (glycoprotein), and large (polymerase) segments. JCV is distributed throughout the United States and Canada and has been isolated from multiple mammals and mosquitoes (1,2). Most infections occur in adults, during the summer, and are asymptomatic, but manifestations can include fever and acute meningoencephalitis (2). Cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis with elevated protein and normal glucose. Diagnosis is made by detection of JCV IgM in serum or CSF and confirmed by plaque-reduction neutralization testing to rule out cross-reactivity with other California serogroup viruses (3). Detection of viral RNA in human CSF has rarely been described, with viremia presumed to be of short duration, so reverse transcription PCR (RT-PCR) is not routinely used for diagnosis (3–5). No specific treatments are available, although intravenous ribavirin has been reported to improve seizures (6). Because of the limited number of cases described, the full range of findings associated with JCV infection is unknown. No fatal cases were reported to the Centers for Disease Control and Prevention (CDC) before 2017, and no autopsy reports have been published (7). The Case-Patient A 56-year-old man from New England with a history of mantle cell lymphoma in remission, receiving maintenance rituximab since 2014, had fatigue, arthralgias, and weight loss in summer 2017. He was empirically treated for Lyme disease without improvement, had progressive insomnia and inattention, and was eventually admitted for workup of rapidly progressive dementia in April 2018. On examination, he had impaired arousal and attention (Montreal Cognitive Assessment score 6 of 30). Cranial nerve, tone, strength, sensory, and reflex examinations were normal. Gait was wide-based and slow without ataxia or parkinsonism. Magnetic resonance imaging of the brain showed mild ventriculomegaly attributed to atrophy but was otherwise unremarkable, without contrast enhancement, cortical diffusion restriction, mass lesions, hemorrhage, or infarction (Figure 1). Electroencephalography showed moderate bihemispheric slowing without epileptiform features. CSF from multiple lumbar punctures showed mild lymphocytic pleocytosis (0–22 leukocytes/μL, 83%–98% lymphocytes), elevated total protein (40–116 mg/dL; reference 10–44 mg/dL), and unremarkable glucose (65–78 mg/dL; reference 40–80 mg/dL) (Appendix Table 1). An extensive infectious, autoimmune, and neurodegenerative disease workup was normal (Appendix Table 2). Figure 1 Brain imaging and autopsy findings in a case of chronic Jamestown Canyon virus (JCV) meningoencephalitis in a patient receiving rituximab, Boston, Massachusetts, USA. A) Brain magnetic resonance imaging T2-weighted fluid-attenuated inversion recovery showed mild atrophy with secondary ventriculomegaly but was otherwise unremarkable. B) Brain positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography showed global hypometabolism. Color scale ranges from blue-green (hypometabolic) to orange-white (hypermetabolic). C, D) Hematoxylin and eosin stained section of cerebral cortex at low magnification shows loss of neurons and perivascular chronic inflammation (C), compared with a JCV-negative control with a normal complement of cortical neurons (D). E, F) Higher-power magnification of cerebral cortex (E) and hippocampus (F) show microgliosis, microglial nodules, and neuronophagia (arrow). G, H) Severe Purkinje cell loss, Bergmann gliois (arrows), and microgliosis (arrowheads) of the molecular layer are present in the cerebellum (G), compared with a JCV-negative control with normal complement of Purkinje cells (H). I, J) Immunohistochemistry shows abundant perivascular, parenchymal, and leptomeningeal CD3+ T cells (I) and is negative for B-cell lineage–specific activator protein positive B cells (J). Panels C, D, I, and J, original magnification ×100; panels E, F, G, and H, original magnification ×200. A CSF sample collected in April 2018 underwent clinical metagenomic next-generation sequencing (mNGS) testing at the University of California–San Francisco (8) and was positive for California encephalitis virus most closely matching JCV, with reads mapping to 2 of the 3 viral genome segments (Appendix Figure 1). Another CSF sample, obtained approximately 3 weeks later in May, was negative for JCV by RT-PCR performed by CDC’s Arboviral Diseases Branch (Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases; Fort Collins, CO, USA); however, concurrent serum JCV RT-PCR was positive. Results of JCV IgM and neutralizing antibody testing were negative for CSF and blood from the samples obtained in May. Concurrent samples had 0% CD20+ circulating lymphocytes (reference 3%–20% lymphocytes), attributed to rituximab treatment, last administered in December 2017. The patient was treated with intravenous immunoglobulin (total 2 g/kg), followed by a 2-week course of favipiravir, an experimental inhibitor of viral RNA polymerase, without improvement. His mental status deteriorated to a comatose state. He was transitioned to comfort care and died in June 2018, ≈1 year after suspected symptom onset. At autopsy, the unfixed brain weighed 1,240 g and appeared grossly normal, with no masses, hemorrhage, infarctions, or herniation. Histologic abnormalities were most prominent in the cerebral cortex (particularly frontal and temporal lobes), cerebellum, and hippocampus; milder changes in basal ganglia, thalamus, and brainstem were observed, including severe loss of neurons, diffuse microgliosis with microglial nodules and neuronophagia, and perivascular and parenchymal chronic inflammation (Figure 1). Leptomeninges showed numerous chronic inflammatory cells. No viral inclusions were identified. There was no evidence of lymphoma. Immunohistochemical staining highlighted abundant perivascular, parenchymal, and leptomeningeal T cells with a complete lack of B cells. Formalin-fixed paraffin-embedded brain tissue was positive for JCV by RT-PCR (performed by CDC’s Arboviral Diagnostic and Reference Laboratory); results were negative for immunohistochemistry for flaviviruses and enteroviruses (performed by CDC’s Infectious Diseases Pathology Branch [Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Atlanta, GA, USA]). Complete or near-complete JCV genomes were recovered from premortem CSF and postmortem cerebellum and cortex tissue (both frozen and formalin-fixed paraffin-embedded) (Table; Appendix Supplementary Methods, Figure 2). Phylogenetic analysis of the small (nucleocapsid) segment showed that sequences from this patient were most closely related to JCV from mosquitoes in Connecticut (Figure 2, panel A) (9). Comparison of JCV genomes between this patient’s CSF, cerebellum, and cortex revealed 27 high-confidence within-patient single-nucleotide polymorphisms (SNPs) (Figure 2, panel B; Appendix Tables 3, 4). For 13 SNPs, the variant present in CSF was different from that in cerebellum and cortex, suggesting evolution over time. For another 4 SNPs, the variant present in cerebellum was different from that in cortex, suggesting compartmentalization. The remaining 10 SNPs could represent either compartmentalization or evolution over time, because only 1 brain tissue (cerebellum or cortex) was sequenced to sufficient depth. Variability was greater in the small segment (nucleocapsid) and medium segment (glycoprotein) than the large segment (polymerase). Table Results of JCV sequencing across samples from an immunocompromised patient with encephalitis, Boston, Massachusetts, USA* Specimen Method Total reads† Unique JCV reads‡ % Genome assembled, by segment§ Mean depth, by genome segment§ Small Medium Large Small Medium Large CSF mNGS, MSSPE 1,917,836,676 894 100 80 90 14.3 3.7 5.3 Cerebellum, frozen mNGS, MSSPE 1,031,252,808 558 98 66 100 9.4 1.3 6.1 Cerebellum, FFPE mNGS, hybrid capture 38,974,996 294 70 56 90 7.1 1.2 3.1 Cortex, frozen mNGS, MSSPE 729,867,496 3,652 100 100 100 61.6 15.2 40.2 Cortex, FFPE mNGS, hybrid capture 101,331,284 518 100 72 91 20.1 2.1 4.5 *Methods detailed in Appendix. CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; mNGS, metagenomic next-generation sequencing; MSSPE, metagenomic sequencing with spiked primer enrichment. †Total reads reflect the number of raw reads that were generated from each sample. ‡Unique JCV reads reflects removal of PCR duplicates and mapping to JCV reference sequences. §Small, 989 nt; Medium, 4,509 nt; Large, 6,960 nt. Figure 2 JCV genome analyses in a case of chronic JCV meningoencephalitis in a patient on rituximab, Boston, Massachusetts, USA. A) Maximum-likelihood phylogenetic tree of the coding region of the JCV small segment (nucleocapsid). Sequences from the patient (bold) were most closely related to a JCV strain isolated from Simsbury, Connecticut, USA (GenBank accession no. EF681842), with ≈70% bootstrap support. Clades A, B1, and B2 are as previously reported (9). B) Single-nucleotide polymorphisms (SNPs) observed between samples from patient in this study. The consensus genome derived from each sample was aligned to a mosquito-derived JCV sequence (GenBank accession nos. HM007356 [S segment], HM007357 [M segment], and HM007358 [L segment], all represented in the figure as HM00735X). For each sample in this study, the light gray bar indicates positions for which there was coverage of >3 reads. Using the sequence derived from CSF as the reference, positions with a SNP are marked with a star; black indicates a synonymous change, and red indicates a nonsynonymous change. Only high-confidence (confirmed) SNPs are shown in this figure; all SNPs observed are shown in Appendix Tables 3, 4. Sequence data is available under National Center for Biotechnology Information BioProject no. PRJNA662969 (GenBank accession nos. MW072986–MW073000). CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; L, large; M, medium; S, small. Conclusions We describe an unusual fatal case of chronic JCV encephalitis in a patient who was being treated with rituximab. In contrast to this case, previously described patients with JCV have had acute illness, and JCV infection is rarely fatal (7,10). The neuropathologic findings in this patient, although nonspecific, are similar to those of a cerebellar biopsy from a patient with JCV encephalitis that showed severe loss of Purkinje and granule cells, diffuse microgliosis of the molecular layer, and leptomeningeal inflammation (5). The lack of distinguishing clinical, radiographic, and pathologic features of JCV underscores the diagnostic utility of clinical mNGS (8). Attributable in part to low incidence and lack of commercially available targeted testing, JCV is often not considered a priori, especially in the setting of chronic progressive neurologic illness. As a further complication, standard clinical testing by serology can be negative in the setting of B-cell–depleting therapy; our patient had negative JCV serologic tests and lack of B lymphocytes by immunohistochemical staining. Similar phenomena have been reported in rituximab-treated patients with other arboviral infections (e.g., Cache Valley orthobunyavirus, Powassan virus, and West Nile virus) who lack detectable antibodies but remain viremic longer than immunocompetent patients, highlighting the importance of nucleic acid–based testing methods (11–13). In addition to diagnosis, mNGS also provides valuable information about pathogen genomics. We report the unique assembly of a JCV genome from human clinical samples, an important advance in the study of JVC pathogenesis, virus evolution, and differences between the enzootic transmission cycle and human infection (14). The functional importance of the identified SNPs could not be evaluated from the genomic data alone; however, none were associated with alterations of potential N-linked glycosylation sites, cysteine bonds, or the conserved fusion domain (15). One SNP that arose between CSF and brain (small segment gA397G; aT109A) also varied between JCV strains with different neurovirulence in mice, although the functional importance is unknown (4). Although treatment options for JCV infection are largely unexplored, response to antiviral drugs probably depends on initiating treatment early in the disease course and reaching therapeutic levels in the CSF before extensive neuronal loss. Thus, broad-spectrum molecular assays such as mNGS could potentially lead to earlier treatment with improved outcomes (8). Appendix Additional information about a fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Acknowledgments We thank the patient’s family for granting permission to publish this information. We also wish to acknowledge contributions by Asmeeta Achari, Sarah Reagan-Steiner, and the molecular pathology and immunohistochemistry teams at CDC’s Infectious Disease Pathology Branch. This study was supported by the National Institutes of Health (grant no. U19AI110818 awarded to P.C.S, grant no. KL2 TR001100 awarded to A.P., and grant no. R33AI129455 awarded to C.Y.C.), the Charles and Helen Schwab Foundation (grant awarded to C.Y.C.), and a Broadnext10 gift from the Broad Institute (awarded to P.C.S.). Dr. Solomon is a neuropathologist at Brigham and Women’s Hospital and Harvard Medical School, in Boston, Massachusetts. His primary research interests include viral infections of the central nervous system. Suggested citation for this article: Solomon IH, Ganesh VS, Yu G, Deng XD, Wilson MR, Miller S, et al. Fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203448 1 These authors contributed equally to this article. 2 These senior authors contributed equally to this article. 3 Current affiliation: Emory University, Atlanta, Georgia, USA.	Intravenous (not otherwise specified)	DrugAdministrationRoute	CC BY	33261720	19,026,565	2021-01
What was the dosage of drug 'HUMAN IMMUNOGLOBULIN G'?	Fatal Case of Chronic Jamestown Canyon Virus Encephalitis Diagnosed by Metagenomic Sequencing in Patient Receiving Rituximab. A 56-year-old man receiving rituximab who had months of neurologic symptoms was found to have Jamestown Canyon virus in cerebrospinal fluid by clinical metagenomic sequencing. The patient died, and postmortem examination revealed extensive neuropathologic abnormalities. Deep sequencing enabled detailed characterization of viral genomes from the cerebrospinal fluid, cerebellum, and cerebral cortex. Jamestown Canyon orthobunyavirus (JCV) is a negative-sense RNA virus in the California serogroup. Its tripartite genome comprises small (nucleocapsid), medium (glycoprotein), and large (polymerase) segments. JCV is distributed throughout the United States and Canada and has been isolated from multiple mammals and mosquitoes (1,2). Most infections occur in adults, during the summer, and are asymptomatic, but manifestations can include fever and acute meningoencephalitis (2). Cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis with elevated protein and normal glucose. Diagnosis is made by detection of JCV IgM in serum or CSF and confirmed by plaque-reduction neutralization testing to rule out cross-reactivity with other California serogroup viruses (3). Detection of viral RNA in human CSF has rarely been described, with viremia presumed to be of short duration, so reverse transcription PCR (RT-PCR) is not routinely used for diagnosis (3–5). No specific treatments are available, although intravenous ribavirin has been reported to improve seizures (6). Because of the limited number of cases described, the full range of findings associated with JCV infection is unknown. No fatal cases were reported to the Centers for Disease Control and Prevention (CDC) before 2017, and no autopsy reports have been published (7). The Case-Patient A 56-year-old man from New England with a history of mantle cell lymphoma in remission, receiving maintenance rituximab since 2014, had fatigue, arthralgias, and weight loss in summer 2017. He was empirically treated for Lyme disease without improvement, had progressive insomnia and inattention, and was eventually admitted for workup of rapidly progressive dementia in April 2018. On examination, he had impaired arousal and attention (Montreal Cognitive Assessment score 6 of 30). Cranial nerve, tone, strength, sensory, and reflex examinations were normal. Gait was wide-based and slow without ataxia or parkinsonism. Magnetic resonance imaging of the brain showed mild ventriculomegaly attributed to atrophy but was otherwise unremarkable, without contrast enhancement, cortical diffusion restriction, mass lesions, hemorrhage, or infarction (Figure 1). Electroencephalography showed moderate bihemispheric slowing without epileptiform features. CSF from multiple lumbar punctures showed mild lymphocytic pleocytosis (0–22 leukocytes/μL, 83%–98% lymphocytes), elevated total protein (40–116 mg/dL; reference 10–44 mg/dL), and unremarkable glucose (65–78 mg/dL; reference 40–80 mg/dL) (Appendix Table 1). An extensive infectious, autoimmune, and neurodegenerative disease workup was normal (Appendix Table 2). Figure 1 Brain imaging and autopsy findings in a case of chronic Jamestown Canyon virus (JCV) meningoencephalitis in a patient receiving rituximab, Boston, Massachusetts, USA. A) Brain magnetic resonance imaging T2-weighted fluid-attenuated inversion recovery showed mild atrophy with secondary ventriculomegaly but was otherwise unremarkable. B) Brain positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography showed global hypometabolism. Color scale ranges from blue-green (hypometabolic) to orange-white (hypermetabolic). C, D) Hematoxylin and eosin stained section of cerebral cortex at low magnification shows loss of neurons and perivascular chronic inflammation (C), compared with a JCV-negative control with a normal complement of cortical neurons (D). E, F) Higher-power magnification of cerebral cortex (E) and hippocampus (F) show microgliosis, microglial nodules, and neuronophagia (arrow). G, H) Severe Purkinje cell loss, Bergmann gliois (arrows), and microgliosis (arrowheads) of the molecular layer are present in the cerebellum (G), compared with a JCV-negative control with normal complement of Purkinje cells (H). I, J) Immunohistochemistry shows abundant perivascular, parenchymal, and leptomeningeal CD3+ T cells (I) and is negative for B-cell lineage–specific activator protein positive B cells (J). Panels C, D, I, and J, original magnification ×100; panels E, F, G, and H, original magnification ×200. A CSF sample collected in April 2018 underwent clinical metagenomic next-generation sequencing (mNGS) testing at the University of California–San Francisco (8) and was positive for California encephalitis virus most closely matching JCV, with reads mapping to 2 of the 3 viral genome segments (Appendix Figure 1). Another CSF sample, obtained approximately 3 weeks later in May, was negative for JCV by RT-PCR performed by CDC’s Arboviral Diseases Branch (Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases; Fort Collins, CO, USA); however, concurrent serum JCV RT-PCR was positive. Results of JCV IgM and neutralizing antibody testing were negative for CSF and blood from the samples obtained in May. Concurrent samples had 0% CD20+ circulating lymphocytes (reference 3%–20% lymphocytes), attributed to rituximab treatment, last administered in December 2017. The patient was treated with intravenous immunoglobulin (total 2 g/kg), followed by a 2-week course of favipiravir, an experimental inhibitor of viral RNA polymerase, without improvement. His mental status deteriorated to a comatose state. He was transitioned to comfort care and died in June 2018, ≈1 year after suspected symptom onset. At autopsy, the unfixed brain weighed 1,240 g and appeared grossly normal, with no masses, hemorrhage, infarctions, or herniation. Histologic abnormalities were most prominent in the cerebral cortex (particularly frontal and temporal lobes), cerebellum, and hippocampus; milder changes in basal ganglia, thalamus, and brainstem were observed, including severe loss of neurons, diffuse microgliosis with microglial nodules and neuronophagia, and perivascular and parenchymal chronic inflammation (Figure 1). Leptomeninges showed numerous chronic inflammatory cells. No viral inclusions were identified. There was no evidence of lymphoma. Immunohistochemical staining highlighted abundant perivascular, parenchymal, and leptomeningeal T cells with a complete lack of B cells. Formalin-fixed paraffin-embedded brain tissue was positive for JCV by RT-PCR (performed by CDC’s Arboviral Diagnostic and Reference Laboratory); results were negative for immunohistochemistry for flaviviruses and enteroviruses (performed by CDC’s Infectious Diseases Pathology Branch [Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Atlanta, GA, USA]). Complete or near-complete JCV genomes were recovered from premortem CSF and postmortem cerebellum and cortex tissue (both frozen and formalin-fixed paraffin-embedded) (Table; Appendix Supplementary Methods, Figure 2). Phylogenetic analysis of the small (nucleocapsid) segment showed that sequences from this patient were most closely related to JCV from mosquitoes in Connecticut (Figure 2, panel A) (9). Comparison of JCV genomes between this patient’s CSF, cerebellum, and cortex revealed 27 high-confidence within-patient single-nucleotide polymorphisms (SNPs) (Figure 2, panel B; Appendix Tables 3, 4). For 13 SNPs, the variant present in CSF was different from that in cerebellum and cortex, suggesting evolution over time. For another 4 SNPs, the variant present in cerebellum was different from that in cortex, suggesting compartmentalization. The remaining 10 SNPs could represent either compartmentalization or evolution over time, because only 1 brain tissue (cerebellum or cortex) was sequenced to sufficient depth. Variability was greater in the small segment (nucleocapsid) and medium segment (glycoprotein) than the large segment (polymerase). Table Results of JCV sequencing across samples from an immunocompromised patient with encephalitis, Boston, Massachusetts, USA* Specimen Method Total reads† Unique JCV reads‡ % Genome assembled, by segment§ Mean depth, by genome segment§ Small Medium Large Small Medium Large CSF mNGS, MSSPE 1,917,836,676 894 100 80 90 14.3 3.7 5.3 Cerebellum, frozen mNGS, MSSPE 1,031,252,808 558 98 66 100 9.4 1.3 6.1 Cerebellum, FFPE mNGS, hybrid capture 38,974,996 294 70 56 90 7.1 1.2 3.1 Cortex, frozen mNGS, MSSPE 729,867,496 3,652 100 100 100 61.6 15.2 40.2 Cortex, FFPE mNGS, hybrid capture 101,331,284 518 100 72 91 20.1 2.1 4.5 *Methods detailed in Appendix. CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; mNGS, metagenomic next-generation sequencing; MSSPE, metagenomic sequencing with spiked primer enrichment. †Total reads reflect the number of raw reads that were generated from each sample. ‡Unique JCV reads reflects removal of PCR duplicates and mapping to JCV reference sequences. §Small, 989 nt; Medium, 4,509 nt; Large, 6,960 nt. Figure 2 JCV genome analyses in a case of chronic JCV meningoencephalitis in a patient on rituximab, Boston, Massachusetts, USA. A) Maximum-likelihood phylogenetic tree of the coding region of the JCV small segment (nucleocapsid). Sequences from the patient (bold) were most closely related to a JCV strain isolated from Simsbury, Connecticut, USA (GenBank accession no. EF681842), with ≈70% bootstrap support. Clades A, B1, and B2 are as previously reported (9). B) Single-nucleotide polymorphisms (SNPs) observed between samples from patient in this study. The consensus genome derived from each sample was aligned to a mosquito-derived JCV sequence (GenBank accession nos. HM007356 [S segment], HM007357 [M segment], and HM007358 [L segment], all represented in the figure as HM00735X). For each sample in this study, the light gray bar indicates positions for which there was coverage of >3 reads. Using the sequence derived from CSF as the reference, positions with a SNP are marked with a star; black indicates a synonymous change, and red indicates a nonsynonymous change. Only high-confidence (confirmed) SNPs are shown in this figure; all SNPs observed are shown in Appendix Tables 3, 4. Sequence data is available under National Center for Biotechnology Information BioProject no. PRJNA662969 (GenBank accession nos. MW072986–MW073000). CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; L, large; M, medium; S, small. Conclusions We describe an unusual fatal case of chronic JCV encephalitis in a patient who was being treated with rituximab. In contrast to this case, previously described patients with JCV have had acute illness, and JCV infection is rarely fatal (7,10). The neuropathologic findings in this patient, although nonspecific, are similar to those of a cerebellar biopsy from a patient with JCV encephalitis that showed severe loss of Purkinje and granule cells, diffuse microgliosis of the molecular layer, and leptomeningeal inflammation (5). The lack of distinguishing clinical, radiographic, and pathologic features of JCV underscores the diagnostic utility of clinical mNGS (8). Attributable in part to low incidence and lack of commercially available targeted testing, JCV is often not considered a priori, especially in the setting of chronic progressive neurologic illness. As a further complication, standard clinical testing by serology can be negative in the setting of B-cell–depleting therapy; our patient had negative JCV serologic tests and lack of B lymphocytes by immunohistochemical staining. Similar phenomena have been reported in rituximab-treated patients with other arboviral infections (e.g., Cache Valley orthobunyavirus, Powassan virus, and West Nile virus) who lack detectable antibodies but remain viremic longer than immunocompetent patients, highlighting the importance of nucleic acid–based testing methods (11–13). In addition to diagnosis, mNGS also provides valuable information about pathogen genomics. We report the unique assembly of a JCV genome from human clinical samples, an important advance in the study of JVC pathogenesis, virus evolution, and differences between the enzootic transmission cycle and human infection (14). The functional importance of the identified SNPs could not be evaluated from the genomic data alone; however, none were associated with alterations of potential N-linked glycosylation sites, cysteine bonds, or the conserved fusion domain (15). One SNP that arose between CSF and brain (small segment gA397G; aT109A) also varied between JCV strains with different neurovirulence in mice, although the functional importance is unknown (4). Although treatment options for JCV infection are largely unexplored, response to antiviral drugs probably depends on initiating treatment early in the disease course and reaching therapeutic levels in the CSF before extensive neuronal loss. Thus, broad-spectrum molecular assays such as mNGS could potentially lead to earlier treatment with improved outcomes (8). Appendix Additional information about a fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Acknowledgments We thank the patient’s family for granting permission to publish this information. We also wish to acknowledge contributions by Asmeeta Achari, Sarah Reagan-Steiner, and the molecular pathology and immunohistochemistry teams at CDC’s Infectious Disease Pathology Branch. This study was supported by the National Institutes of Health (grant no. U19AI110818 awarded to P.C.S, grant no. KL2 TR001100 awarded to A.P., and grant no. R33AI129455 awarded to C.Y.C.), the Charles and Helen Schwab Foundation (grant awarded to C.Y.C.), and a Broadnext10 gift from the Broad Institute (awarded to P.C.S.). Dr. Solomon is a neuropathologist at Brigham and Women’s Hospital and Harvard Medical School, in Boston, Massachusetts. His primary research interests include viral infections of the central nervous system. Suggested citation for this article: Solomon IH, Ganesh VS, Yu G, Deng XD, Wilson MR, Miller S, et al. Fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203448 1 These authors contributed equally to this article. 2 These senior authors contributed equally to this article. 3 Current affiliation: Emory University, Atlanta, Georgia, USA.	2 GRAM PER KILOGRAM	DrugDosageText	CC BY	33261720	19,026,565	2021-01
What was the outcome of reaction 'Drug ineffective for unapproved indication'?	Fatal Case of Chronic Jamestown Canyon Virus Encephalitis Diagnosed by Metagenomic Sequencing in Patient Receiving Rituximab. A 56-year-old man receiving rituximab who had months of neurologic symptoms was found to have Jamestown Canyon virus in cerebrospinal fluid by clinical metagenomic sequencing. The patient died, and postmortem examination revealed extensive neuropathologic abnormalities. Deep sequencing enabled detailed characterization of viral genomes from the cerebrospinal fluid, cerebellum, and cerebral cortex. Jamestown Canyon orthobunyavirus (JCV) is a negative-sense RNA virus in the California serogroup. Its tripartite genome comprises small (nucleocapsid), medium (glycoprotein), and large (polymerase) segments. JCV is distributed throughout the United States and Canada and has been isolated from multiple mammals and mosquitoes (1,2). Most infections occur in adults, during the summer, and are asymptomatic, but manifestations can include fever and acute meningoencephalitis (2). Cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis with elevated protein and normal glucose. Diagnosis is made by detection of JCV IgM in serum or CSF and confirmed by plaque-reduction neutralization testing to rule out cross-reactivity with other California serogroup viruses (3). Detection of viral RNA in human CSF has rarely been described, with viremia presumed to be of short duration, so reverse transcription PCR (RT-PCR) is not routinely used for diagnosis (3–5). No specific treatments are available, although intravenous ribavirin has been reported to improve seizures (6). Because of the limited number of cases described, the full range of findings associated with JCV infection is unknown. No fatal cases were reported to the Centers for Disease Control and Prevention (CDC) before 2017, and no autopsy reports have been published (7). The Case-Patient A 56-year-old man from New England with a history of mantle cell lymphoma in remission, receiving maintenance rituximab since 2014, had fatigue, arthralgias, and weight loss in summer 2017. He was empirically treated for Lyme disease without improvement, had progressive insomnia and inattention, and was eventually admitted for workup of rapidly progressive dementia in April 2018. On examination, he had impaired arousal and attention (Montreal Cognitive Assessment score 6 of 30). Cranial nerve, tone, strength, sensory, and reflex examinations were normal. Gait was wide-based and slow without ataxia or parkinsonism. Magnetic resonance imaging of the brain showed mild ventriculomegaly attributed to atrophy but was otherwise unremarkable, without contrast enhancement, cortical diffusion restriction, mass lesions, hemorrhage, or infarction (Figure 1). Electroencephalography showed moderate bihemispheric slowing without epileptiform features. CSF from multiple lumbar punctures showed mild lymphocytic pleocytosis (0–22 leukocytes/μL, 83%–98% lymphocytes), elevated total protein (40–116 mg/dL; reference 10–44 mg/dL), and unremarkable glucose (65–78 mg/dL; reference 40–80 mg/dL) (Appendix Table 1). An extensive infectious, autoimmune, and neurodegenerative disease workup was normal (Appendix Table 2). Figure 1 Brain imaging and autopsy findings in a case of chronic Jamestown Canyon virus (JCV) meningoencephalitis in a patient receiving rituximab, Boston, Massachusetts, USA. A) Brain magnetic resonance imaging T2-weighted fluid-attenuated inversion recovery showed mild atrophy with secondary ventriculomegaly but was otherwise unremarkable. B) Brain positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography showed global hypometabolism. Color scale ranges from blue-green (hypometabolic) to orange-white (hypermetabolic). C, D) Hematoxylin and eosin stained section of cerebral cortex at low magnification shows loss of neurons and perivascular chronic inflammation (C), compared with a JCV-negative control with a normal complement of cortical neurons (D). E, F) Higher-power magnification of cerebral cortex (E) and hippocampus (F) show microgliosis, microglial nodules, and neuronophagia (arrow). G, H) Severe Purkinje cell loss, Bergmann gliois (arrows), and microgliosis (arrowheads) of the molecular layer are present in the cerebellum (G), compared with a JCV-negative control with normal complement of Purkinje cells (H). I, J) Immunohistochemistry shows abundant perivascular, parenchymal, and leptomeningeal CD3+ T cells (I) and is negative for B-cell lineage–specific activator protein positive B cells (J). Panels C, D, I, and J, original magnification ×100; panels E, F, G, and H, original magnification ×200. A CSF sample collected in April 2018 underwent clinical metagenomic next-generation sequencing (mNGS) testing at the University of California–San Francisco (8) and was positive for California encephalitis virus most closely matching JCV, with reads mapping to 2 of the 3 viral genome segments (Appendix Figure 1). Another CSF sample, obtained approximately 3 weeks later in May, was negative for JCV by RT-PCR performed by CDC’s Arboviral Diseases Branch (Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases; Fort Collins, CO, USA); however, concurrent serum JCV RT-PCR was positive. Results of JCV IgM and neutralizing antibody testing were negative for CSF and blood from the samples obtained in May. Concurrent samples had 0% CD20+ circulating lymphocytes (reference 3%–20% lymphocytes), attributed to rituximab treatment, last administered in December 2017. The patient was treated with intravenous immunoglobulin (total 2 g/kg), followed by a 2-week course of favipiravir, an experimental inhibitor of viral RNA polymerase, without improvement. His mental status deteriorated to a comatose state. He was transitioned to comfort care and died in June 2018, ≈1 year after suspected symptom onset. At autopsy, the unfixed brain weighed 1,240 g and appeared grossly normal, with no masses, hemorrhage, infarctions, or herniation. Histologic abnormalities were most prominent in the cerebral cortex (particularly frontal and temporal lobes), cerebellum, and hippocampus; milder changes in basal ganglia, thalamus, and brainstem were observed, including severe loss of neurons, diffuse microgliosis with microglial nodules and neuronophagia, and perivascular and parenchymal chronic inflammation (Figure 1). Leptomeninges showed numerous chronic inflammatory cells. No viral inclusions were identified. There was no evidence of lymphoma. Immunohistochemical staining highlighted abundant perivascular, parenchymal, and leptomeningeal T cells with a complete lack of B cells. Formalin-fixed paraffin-embedded brain tissue was positive for JCV by RT-PCR (performed by CDC’s Arboviral Diagnostic and Reference Laboratory); results were negative for immunohistochemistry for flaviviruses and enteroviruses (performed by CDC’s Infectious Diseases Pathology Branch [Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Atlanta, GA, USA]). Complete or near-complete JCV genomes were recovered from premortem CSF and postmortem cerebellum and cortex tissue (both frozen and formalin-fixed paraffin-embedded) (Table; Appendix Supplementary Methods, Figure 2). Phylogenetic analysis of the small (nucleocapsid) segment showed that sequences from this patient were most closely related to JCV from mosquitoes in Connecticut (Figure 2, panel A) (9). Comparison of JCV genomes between this patient’s CSF, cerebellum, and cortex revealed 27 high-confidence within-patient single-nucleotide polymorphisms (SNPs) (Figure 2, panel B; Appendix Tables 3, 4). For 13 SNPs, the variant present in CSF was different from that in cerebellum and cortex, suggesting evolution over time. For another 4 SNPs, the variant present in cerebellum was different from that in cortex, suggesting compartmentalization. The remaining 10 SNPs could represent either compartmentalization or evolution over time, because only 1 brain tissue (cerebellum or cortex) was sequenced to sufficient depth. Variability was greater in the small segment (nucleocapsid) and medium segment (glycoprotein) than the large segment (polymerase). Table Results of JCV sequencing across samples from an immunocompromised patient with encephalitis, Boston, Massachusetts, USA* Specimen Method Total reads† Unique JCV reads‡ % Genome assembled, by segment§ Mean depth, by genome segment§ Small Medium Large Small Medium Large CSF mNGS, MSSPE 1,917,836,676 894 100 80 90 14.3 3.7 5.3 Cerebellum, frozen mNGS, MSSPE 1,031,252,808 558 98 66 100 9.4 1.3 6.1 Cerebellum, FFPE mNGS, hybrid capture 38,974,996 294 70 56 90 7.1 1.2 3.1 Cortex, frozen mNGS, MSSPE 729,867,496 3,652 100 100 100 61.6 15.2 40.2 Cortex, FFPE mNGS, hybrid capture 101,331,284 518 100 72 91 20.1 2.1 4.5 *Methods detailed in Appendix. CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; mNGS, metagenomic next-generation sequencing; MSSPE, metagenomic sequencing with spiked primer enrichment. †Total reads reflect the number of raw reads that were generated from each sample. ‡Unique JCV reads reflects removal of PCR duplicates and mapping to JCV reference sequences. §Small, 989 nt; Medium, 4,509 nt; Large, 6,960 nt. Figure 2 JCV genome analyses in a case of chronic JCV meningoencephalitis in a patient on rituximab, Boston, Massachusetts, USA. A) Maximum-likelihood phylogenetic tree of the coding region of the JCV small segment (nucleocapsid). Sequences from the patient (bold) were most closely related to a JCV strain isolated from Simsbury, Connecticut, USA (GenBank accession no. EF681842), with ≈70% bootstrap support. Clades A, B1, and B2 are as previously reported (9). B) Single-nucleotide polymorphisms (SNPs) observed between samples from patient in this study. The consensus genome derived from each sample was aligned to a mosquito-derived JCV sequence (GenBank accession nos. HM007356 [S segment], HM007357 [M segment], and HM007358 [L segment], all represented in the figure as HM00735X). For each sample in this study, the light gray bar indicates positions for which there was coverage of >3 reads. Using the sequence derived from CSF as the reference, positions with a SNP are marked with a star; black indicates a synonymous change, and red indicates a nonsynonymous change. Only high-confidence (confirmed) SNPs are shown in this figure; all SNPs observed are shown in Appendix Tables 3, 4. Sequence data is available under National Center for Biotechnology Information BioProject no. PRJNA662969 (GenBank accession nos. MW072986–MW073000). CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; L, large; M, medium; S, small. Conclusions We describe an unusual fatal case of chronic JCV encephalitis in a patient who was being treated with rituximab. In contrast to this case, previously described patients with JCV have had acute illness, and JCV infection is rarely fatal (7,10). The neuropathologic findings in this patient, although nonspecific, are similar to those of a cerebellar biopsy from a patient with JCV encephalitis that showed severe loss of Purkinje and granule cells, diffuse microgliosis of the molecular layer, and leptomeningeal inflammation (5). The lack of distinguishing clinical, radiographic, and pathologic features of JCV underscores the diagnostic utility of clinical mNGS (8). Attributable in part to low incidence and lack of commercially available targeted testing, JCV is often not considered a priori, especially in the setting of chronic progressive neurologic illness. As a further complication, standard clinical testing by serology can be negative in the setting of B-cell–depleting therapy; our patient had negative JCV serologic tests and lack of B lymphocytes by immunohistochemical staining. Similar phenomena have been reported in rituximab-treated patients with other arboviral infections (e.g., Cache Valley orthobunyavirus, Powassan virus, and West Nile virus) who lack detectable antibodies but remain viremic longer than immunocompetent patients, highlighting the importance of nucleic acid–based testing methods (11–13). In addition to diagnosis, mNGS also provides valuable information about pathogen genomics. We report the unique assembly of a JCV genome from human clinical samples, an important advance in the study of JVC pathogenesis, virus evolution, and differences between the enzootic transmission cycle and human infection (14). The functional importance of the identified SNPs could not be evaluated from the genomic data alone; however, none were associated with alterations of potential N-linked glycosylation sites, cysteine bonds, or the conserved fusion domain (15). One SNP that arose between CSF and brain (small segment gA397G; aT109A) also varied between JCV strains with different neurovirulence in mice, although the functional importance is unknown (4). Although treatment options for JCV infection are largely unexplored, response to antiviral drugs probably depends on initiating treatment early in the disease course and reaching therapeutic levels in the CSF before extensive neuronal loss. Thus, broad-spectrum molecular assays such as mNGS could potentially lead to earlier treatment with improved outcomes (8). Appendix Additional information about a fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Acknowledgments We thank the patient’s family for granting permission to publish this information. We also wish to acknowledge contributions by Asmeeta Achari, Sarah Reagan-Steiner, and the molecular pathology and immunohistochemistry teams at CDC’s Infectious Disease Pathology Branch. This study was supported by the National Institutes of Health (grant no. U19AI110818 awarded to P.C.S, grant no. KL2 TR001100 awarded to A.P., and grant no. R33AI129455 awarded to C.Y.C.), the Charles and Helen Schwab Foundation (grant awarded to C.Y.C.), and a Broadnext10 gift from the Broad Institute (awarded to P.C.S.). Dr. Solomon is a neuropathologist at Brigham and Women’s Hospital and Harvard Medical School, in Boston, Massachusetts. His primary research interests include viral infections of the central nervous system. Suggested citation for this article: Solomon IH, Ganesh VS, Yu G, Deng XD, Wilson MR, Miller S, et al. Fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203448 1 These authors contributed equally to this article. 2 These senior authors contributed equally to this article. 3 Current affiliation: Emory University, Atlanta, Georgia, USA.	Fatal	ReactionOutcome	CC BY	33261720	19,026,565	2021-01
What was the outcome of reaction 'Off label use'?	Fatal Case of Chronic Jamestown Canyon Virus Encephalitis Diagnosed by Metagenomic Sequencing in Patient Receiving Rituximab. A 56-year-old man receiving rituximab who had months of neurologic symptoms was found to have Jamestown Canyon virus in cerebrospinal fluid by clinical metagenomic sequencing. The patient died, and postmortem examination revealed extensive neuropathologic abnormalities. Deep sequencing enabled detailed characterization of viral genomes from the cerebrospinal fluid, cerebellum, and cerebral cortex. Jamestown Canyon orthobunyavirus (JCV) is a negative-sense RNA virus in the California serogroup. Its tripartite genome comprises small (nucleocapsid), medium (glycoprotein), and large (polymerase) segments. JCV is distributed throughout the United States and Canada and has been isolated from multiple mammals and mosquitoes (1,2). Most infections occur in adults, during the summer, and are asymptomatic, but manifestations can include fever and acute meningoencephalitis (2). Cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis with elevated protein and normal glucose. Diagnosis is made by detection of JCV IgM in serum or CSF and confirmed by plaque-reduction neutralization testing to rule out cross-reactivity with other California serogroup viruses (3). Detection of viral RNA in human CSF has rarely been described, with viremia presumed to be of short duration, so reverse transcription PCR (RT-PCR) is not routinely used for diagnosis (3–5). No specific treatments are available, although intravenous ribavirin has been reported to improve seizures (6). Because of the limited number of cases described, the full range of findings associated with JCV infection is unknown. No fatal cases were reported to the Centers for Disease Control and Prevention (CDC) before 2017, and no autopsy reports have been published (7). The Case-Patient A 56-year-old man from New England with a history of mantle cell lymphoma in remission, receiving maintenance rituximab since 2014, had fatigue, arthralgias, and weight loss in summer 2017. He was empirically treated for Lyme disease without improvement, had progressive insomnia and inattention, and was eventually admitted for workup of rapidly progressive dementia in April 2018. On examination, he had impaired arousal and attention (Montreal Cognitive Assessment score 6 of 30). Cranial nerve, tone, strength, sensory, and reflex examinations were normal. Gait was wide-based and slow without ataxia or parkinsonism. Magnetic resonance imaging of the brain showed mild ventriculomegaly attributed to atrophy but was otherwise unremarkable, without contrast enhancement, cortical diffusion restriction, mass lesions, hemorrhage, or infarction (Figure 1). Electroencephalography showed moderate bihemispheric slowing without epileptiform features. CSF from multiple lumbar punctures showed mild lymphocytic pleocytosis (0–22 leukocytes/μL, 83%–98% lymphocytes), elevated total protein (40–116 mg/dL; reference 10–44 mg/dL), and unremarkable glucose (65–78 mg/dL; reference 40–80 mg/dL) (Appendix Table 1). An extensive infectious, autoimmune, and neurodegenerative disease workup was normal (Appendix Table 2). Figure 1 Brain imaging and autopsy findings in a case of chronic Jamestown Canyon virus (JCV) meningoencephalitis in a patient receiving rituximab, Boston, Massachusetts, USA. A) Brain magnetic resonance imaging T2-weighted fluid-attenuated inversion recovery showed mild atrophy with secondary ventriculomegaly but was otherwise unremarkable. B) Brain positron emission tomography with 2-deoxy-2-[fluorine-18] fluoro-D-glucose integrated with computed tomography showed global hypometabolism. Color scale ranges from blue-green (hypometabolic) to orange-white (hypermetabolic). C, D) Hematoxylin and eosin stained section of cerebral cortex at low magnification shows loss of neurons and perivascular chronic inflammation (C), compared with a JCV-negative control with a normal complement of cortical neurons (D). E, F) Higher-power magnification of cerebral cortex (E) and hippocampus (F) show microgliosis, microglial nodules, and neuronophagia (arrow). G, H) Severe Purkinje cell loss, Bergmann gliois (arrows), and microgliosis (arrowheads) of the molecular layer are present in the cerebellum (G), compared with a JCV-negative control with normal complement of Purkinje cells (H). I, J) Immunohistochemistry shows abundant perivascular, parenchymal, and leptomeningeal CD3+ T cells (I) and is negative for B-cell lineage–specific activator protein positive B cells (J). Panels C, D, I, and J, original magnification ×100; panels E, F, G, and H, original magnification ×200. A CSF sample collected in April 2018 underwent clinical metagenomic next-generation sequencing (mNGS) testing at the University of California–San Francisco (8) and was positive for California encephalitis virus most closely matching JCV, with reads mapping to 2 of the 3 viral genome segments (Appendix Figure 1). Another CSF sample, obtained approximately 3 weeks later in May, was negative for JCV by RT-PCR performed by CDC’s Arboviral Diseases Branch (Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases; Fort Collins, CO, USA); however, concurrent serum JCV RT-PCR was positive. Results of JCV IgM and neutralizing antibody testing were negative for CSF and blood from the samples obtained in May. Concurrent samples had 0% CD20+ circulating lymphocytes (reference 3%–20% lymphocytes), attributed to rituximab treatment, last administered in December 2017. The patient was treated with intravenous immunoglobulin (total 2 g/kg), followed by a 2-week course of favipiravir, an experimental inhibitor of viral RNA polymerase, without improvement. His mental status deteriorated to a comatose state. He was transitioned to comfort care and died in June 2018, ≈1 year after suspected symptom onset. At autopsy, the unfixed brain weighed 1,240 g and appeared grossly normal, with no masses, hemorrhage, infarctions, or herniation. Histologic abnormalities were most prominent in the cerebral cortex (particularly frontal and temporal lobes), cerebellum, and hippocampus; milder changes in basal ganglia, thalamus, and brainstem were observed, including severe loss of neurons, diffuse microgliosis with microglial nodules and neuronophagia, and perivascular and parenchymal chronic inflammation (Figure 1). Leptomeninges showed numerous chronic inflammatory cells. No viral inclusions were identified. There was no evidence of lymphoma. Immunohistochemical staining highlighted abundant perivascular, parenchymal, and leptomeningeal T cells with a complete lack of B cells. Formalin-fixed paraffin-embedded brain tissue was positive for JCV by RT-PCR (performed by CDC’s Arboviral Diagnostic and Reference Laboratory); results were negative for immunohistochemistry for flaviviruses and enteroviruses (performed by CDC’s Infectious Diseases Pathology Branch [Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Atlanta, GA, USA]). Complete or near-complete JCV genomes were recovered from premortem CSF and postmortem cerebellum and cortex tissue (both frozen and formalin-fixed paraffin-embedded) (Table; Appendix Supplementary Methods, Figure 2). Phylogenetic analysis of the small (nucleocapsid) segment showed that sequences from this patient were most closely related to JCV from mosquitoes in Connecticut (Figure 2, panel A) (9). Comparison of JCV genomes between this patient’s CSF, cerebellum, and cortex revealed 27 high-confidence within-patient single-nucleotide polymorphisms (SNPs) (Figure 2, panel B; Appendix Tables 3, 4). For 13 SNPs, the variant present in CSF was different from that in cerebellum and cortex, suggesting evolution over time. For another 4 SNPs, the variant present in cerebellum was different from that in cortex, suggesting compartmentalization. The remaining 10 SNPs could represent either compartmentalization or evolution over time, because only 1 brain tissue (cerebellum or cortex) was sequenced to sufficient depth. Variability was greater in the small segment (nucleocapsid) and medium segment (glycoprotein) than the large segment (polymerase). Table Results of JCV sequencing across samples from an immunocompromised patient with encephalitis, Boston, Massachusetts, USA* Specimen Method Total reads† Unique JCV reads‡ % Genome assembled, by segment§ Mean depth, by genome segment§ Small Medium Large Small Medium Large CSF mNGS, MSSPE 1,917,836,676 894 100 80 90 14.3 3.7 5.3 Cerebellum, frozen mNGS, MSSPE 1,031,252,808 558 98 66 100 9.4 1.3 6.1 Cerebellum, FFPE mNGS, hybrid capture 38,974,996 294 70 56 90 7.1 1.2 3.1 Cortex, frozen mNGS, MSSPE 729,867,496 3,652 100 100 100 61.6 15.2 40.2 Cortex, FFPE mNGS, hybrid capture 101,331,284 518 100 72 91 20.1 2.1 4.5 *Methods detailed in Appendix. CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; mNGS, metagenomic next-generation sequencing; MSSPE, metagenomic sequencing with spiked primer enrichment. †Total reads reflect the number of raw reads that were generated from each sample. ‡Unique JCV reads reflects removal of PCR duplicates and mapping to JCV reference sequences. §Small, 989 nt; Medium, 4,509 nt; Large, 6,960 nt. Figure 2 JCV genome analyses in a case of chronic JCV meningoencephalitis in a patient on rituximab, Boston, Massachusetts, USA. A) Maximum-likelihood phylogenetic tree of the coding region of the JCV small segment (nucleocapsid). Sequences from the patient (bold) were most closely related to a JCV strain isolated from Simsbury, Connecticut, USA (GenBank accession no. EF681842), with ≈70% bootstrap support. Clades A, B1, and B2 are as previously reported (9). B) Single-nucleotide polymorphisms (SNPs) observed between samples from patient in this study. The consensus genome derived from each sample was aligned to a mosquito-derived JCV sequence (GenBank accession nos. HM007356 [S segment], HM007357 [M segment], and HM007358 [L segment], all represented in the figure as HM00735X). For each sample in this study, the light gray bar indicates positions for which there was coverage of >3 reads. Using the sequence derived from CSF as the reference, positions with a SNP are marked with a star; black indicates a synonymous change, and red indicates a nonsynonymous change. Only high-confidence (confirmed) SNPs are shown in this figure; all SNPs observed are shown in Appendix Tables 3, 4. Sequence data is available under National Center for Biotechnology Information BioProject no. PRJNA662969 (GenBank accession nos. MW072986–MW073000). CSF, cerebrospinal fluid; FFPE, formalin-fixed, paraffin-embedded; JCV, Jamestown Canyon virus; L, large; M, medium; S, small. Conclusions We describe an unusual fatal case of chronic JCV encephalitis in a patient who was being treated with rituximab. In contrast to this case, previously described patients with JCV have had acute illness, and JCV infection is rarely fatal (7,10). The neuropathologic findings in this patient, although nonspecific, are similar to those of a cerebellar biopsy from a patient with JCV encephalitis that showed severe loss of Purkinje and granule cells, diffuse microgliosis of the molecular layer, and leptomeningeal inflammation (5). The lack of distinguishing clinical, radiographic, and pathologic features of JCV underscores the diagnostic utility of clinical mNGS (8). Attributable in part to low incidence and lack of commercially available targeted testing, JCV is often not considered a priori, especially in the setting of chronic progressive neurologic illness. As a further complication, standard clinical testing by serology can be negative in the setting of B-cell–depleting therapy; our patient had negative JCV serologic tests and lack of B lymphocytes by immunohistochemical staining. Similar phenomena have been reported in rituximab-treated patients with other arboviral infections (e.g., Cache Valley orthobunyavirus, Powassan virus, and West Nile virus) who lack detectable antibodies but remain viremic longer than immunocompetent patients, highlighting the importance of nucleic acid–based testing methods (11–13). In addition to diagnosis, mNGS also provides valuable information about pathogen genomics. We report the unique assembly of a JCV genome from human clinical samples, an important advance in the study of JVC pathogenesis, virus evolution, and differences between the enzootic transmission cycle and human infection (14). The functional importance of the identified SNPs could not be evaluated from the genomic data alone; however, none were associated with alterations of potential N-linked glycosylation sites, cysteine bonds, or the conserved fusion domain (15). One SNP that arose between CSF and brain (small segment gA397G; aT109A) also varied between JCV strains with different neurovirulence in mice, although the functional importance is unknown (4). Although treatment options for JCV infection are largely unexplored, response to antiviral drugs probably depends on initiating treatment early in the disease course and reaching therapeutic levels in the CSF before extensive neuronal loss. Thus, broad-spectrum molecular assays such as mNGS could potentially lead to earlier treatment with improved outcomes (8). Appendix Additional information about a fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Acknowledgments We thank the patient’s family for granting permission to publish this information. We also wish to acknowledge contributions by Asmeeta Achari, Sarah Reagan-Steiner, and the molecular pathology and immunohistochemistry teams at CDC’s Infectious Disease Pathology Branch. This study was supported by the National Institutes of Health (grant no. U19AI110818 awarded to P.C.S, grant no. KL2 TR001100 awarded to A.P., and grant no. R33AI129455 awarded to C.Y.C.), the Charles and Helen Schwab Foundation (grant awarded to C.Y.C.), and a Broadnext10 gift from the Broad Institute (awarded to P.C.S.). Dr. Solomon is a neuropathologist at Brigham and Women’s Hospital and Harvard Medical School, in Boston, Massachusetts. His primary research interests include viral infections of the central nervous system. Suggested citation for this article: Solomon IH, Ganesh VS, Yu G, Deng XD, Wilson MR, Miller S, et al. Fatal case of chronic Jamestown Canyon virus encephalitis diagnosed by metagenomic sequencing in a patient receiving rituximab. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203448 1 These authors contributed equally to this article. 2 These senior authors contributed equally to this article. 3 Current affiliation: Emory University, Atlanta, Georgia, USA.	Fatal	ReactionOutcome	CC BY	33261720	19,026,565	2021-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acquired chromosomal abnormality'.	Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial. Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse. Introduction Multiple myeloma (MM) is caused by the malignant clonal expansion of plasma cells in the bone marrow [1]. Approximately 40% of MM tumors harbor chromosome t(4;14), t(11;14), or t(14;16)/t(14;20) translocations, which result in overexpression of oncogenes (including WHSC1/MMSET/NSD2, FGFR3, CCND1, MAF, and MAFB) through juxtaposition to the immunoglobulin heavy-chain locus [2, 3]. Other MM tumors exhibit hyperdiploidy (HRD), which is considered an alternative initiating event. Increased expression of CCND1 in t(11;14) and HRD and increased CCND2 expression in t(4;14), t(14;16)/t(14;20), and HRD are unifying downstream consequences of initiating lesions [4–10]. Recent next-generation sequencing projects have provided insight into the sub-clonal complexity of tumor progression in MM [11–14]. However, few recurrent single nucleotide changes have been reported to be associated with disease relapse, notably sub-clonal mutations of cereblon in immunomodulatory drug (IMiD) treated patients. Knowledge about their prognostic impact remains limited [15]. In contrast, several large-scale chromosomal abnormalities, including gain(1q), del(1p), and del(17p) have been shown to be acquired during tumor progression, but their association with tumor subtype, treatment and outcome is not well understood [11, 16]. Recent studies of the relationship between copy number aberrations (CNAs) and progression of MM have largely been based on short-read sequencing or FISH. Importantly, few studies have been performed on patients from a randomized clinical trial and the impact of therapy on acquisition of CNAs remains unclear [15, 16]. To gain insight into the relationship between CNAs and progression of MM we performed virtual karyotyping of all chromosomes and targeted hotspot profiling using digital multiplexed ligation-dependent probe amplification (digitalMLPA) in matched diagnosis–relapse tumor pairs in 178 UK NCRI Myeloma XI trial patients [17]. We show that acquisition of CNAs is strongly correlated with MM subgroups. Additionally, a number of acquired changes have independent predictive value for defining patient outcome. Material and methods Patients We studied 178 newly diagnosed MM patients enrolled in UK NCRI Myeloma XI (ISRCTN49407852) for which high quality bone marrow tumor material at both presentation and relapse was available. First outcomes of the trial have been published recently [17]. Briefly, patients were initially randomized to triplet induction with thalidomide (CTD), lenalidomide (CRD), or carfilzomib and lenalidomide (KCRD; transplant-eligible patients only) in combination with cyclophosphamide and dexamethasone. Insufficient responders (partial or minimal response) were randomized to cyclophosphamide, bortezomib and dexamethasone (CVD) vs. no intensification and nonresponders (stable or progressive disease) received CVD. Younger, fitter patients received high-dose melphalan (HDMEL) and autologous stem-cell transplantation, patients were randomized to receive lenalidomide, lenalidomide plus vorinostat, or observation. Maintenance treatment continued until progressive disease in the absence of toxicity (Supplementary Fig. 1). Median time to progression was 20.7 months (range 3.7–71.9 months) and median follow-up 47.0 months. Baseline characteristics are summarized in Supplementary Table 1. The frequency of chromosomal aberrations detectable in the 178 patients at presentation were representative of the overall trial cohort (Supplementary Table 2) [4]. For all patients CD138-positive tumor cells were immunomagnetically selected at presentation and relapse and quality controlled for tumor cell purity (>95%), DNA and RNA were extracted using QIAGEN (Hilden, Germany) Allprep kits. Additional molecular quality control including longitudinal consistency for IgD deletion status was performed for all cases. Matched identity of presentation-relapse pairs was confirmed using single nucleotide and/or insertion/deletion polymorphisms assayed by digitalMLPA D006-X2 for all samples. All patients provided written informed consent. The study was approved by the UK National Research Ethics Service, research ethics committees at participating centers and the UK Medicines and Healthcare Products Regulatory Agency. Translocation and copy number profiling Multiplexed qRT-PCR was used to determine t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20) status in tumors, based on the translocation cyclin D (TC) classification system as previously described [5, 18]. Targeted genome wide CNA status at presentation and relapse in each patient was assessed with a newly developed research version of D006-X2 Multiple Myeloma digitalMLPA probemix, as previously described (Supplementary Methods) [19, 20]. Details of each probe and their respective genomic positions are provided in Supplementary Table 3. CNAs involving sex chromosomes were not considered. CNAs were called if ≥50% of probes mapping to an individual gene or genomic region deviated from normal diploid pattern. Statistical analyses Analyses were performed in R version 3.5.2 using “dplyr”, “tidyr”, “stats”, “survival” and “survminer”, “ComplexHeatmap” and “ggpubr” packages. The association between categorical variables was examined using Fishers exact test and between continuous variables using the Wilcoxon signed-rank test. Progression-free survival (PFS) was defined as time from induction randomization to progression, according to International Myeloma Working Group criteria, or death of any cause. Overall survival (OS) was time from induction randomization to death of any cause. Cox proportional hazards (PH) regression was used to estimate univariate and multivariable hazard ratios (HRs) and 95% confidence intervals (CI). To examine the predictive value of evolution in CNA status for subsequent therapy, high-risk CNA were considered as time dependent covariates within the multivariate model. The PH assumption was tested to investigate whether time dependent covariate effects persisted irrespective of time of acquisition (Supplementary Methods). Multivariate covariates included t(4;14), t(14;16), del(1p), gain(1q), del(17p) and treatment pathway (transplant eligible vs. not). This is relevant because, although the median follow-up of this cohort is long, the inherent requirement of a relapse biopsy excludes the longest responders from our analyses as they are still on active trial medication or observation with no evidence of disease progression. Differences between Kaplan–Meier survival curves was assessed using the log-rank test. A two-sided P value of ≤0.05 was considered statistically significant. Results Acquisition of new CNAs is a feature of relapse Relapse was associated with the acquisition of new CNAs in 87.1% of tumors, most (73.2%) being large-scale chromosome changes. Across all patients, relapse was associated with a higher number of CNAs: median 11.5 (range 0–34) vs. median 12 (range 0–29) (P = 0.0058). As previously well-documented [16, 21], IGH translocations were clonal at presentation and their status did not change at relapse. The most frequent chromosomal changes associated with relapse were gain or amplification of 1q (19%), del(13q) (10%), gain or amplification of 11q (9%) and del(17p)/TP53 in (8%) (Fig. 1; Supplementary Table 2). Although not common, some clonal CNAs detectable at presentation were not detectable at relapse, in particular gain of odd numbered chromosomes in HRD tumors (Supplementary Fig. 2).Fig. 1 Recurrent chromosomal and sub-chromosomal CNA changes at relapse. A Frequency of CNAs emerging at relapse affecting chromosome arms, including new gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green) plotted as a bar graph. B Bar graph showing frequency of 1q, 13q, and 17p CNAs, including gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green), at presentation and relapse. C Heat map of evolving chromosome 1 CNAs at relapse, 63 tumors with change in this region at relapse. On the left (Y-axis) dendrogram representing unsupervised clustering analysis of emerging CNAs in areas interrogated by digitalMLPA probes, which are annotated with gene names and chromosomal location below (X-axis). Change per probe and tumor color-coded as per scale representing normalized digitalMLPA copy number ratios with 1.0 equivalent to normal/diploid. Evolution of sub-chromosomal aberrations In contrast to 1q gain, which generally involved the whole chromosomal arm, clonal 1p deletions tended to be sub-chromosomal (Fig. 1): 1p32.3 deletion (9/178; 5.1%) implicating CDKN2C or 1p12 implicating FAM46C (4/178; 2.2%). In nine of 22 tumors with 1p12 (FAM46C) deletion at diagnosis, the deletion was not clonally detectable at relapse; in contrast all but one of the 8 presentation 1p32.3 (CDKN2C) deletions were detectable at relapse. Focal gain at relapse also affected 8q24.21, involving the MYC locus, in 10/178 (5.6%) tumors. In three of 15 tumors with MYC gain at presentation, reversion to diploid status was a feature of relapse. Sub-chromosomal CNAs involving IMiD response genes—CRBN (3p26.2), IKZF1 (7p12.2), IKZF3 (17q12), and IRF4 (6p25.3)—were infrequent (Supplementary Fig. 3). Most were detectable in tumors relapsing off therapy (no maintenance); only 2 out of 10 were a feature of tumors from patients in receipt of lenalidomide maintenance (1 deletion of CRBN; 1 gain IRF4). Evolution of driver copy number aberrations We next examined for clonal emergence at relapse of sub-clonal changes at diagnosis, focusing on the most frequent drivers—gain(1q) and del(17p). We and others showed before that calling of CNAs using conservative high confidence MLPA cutoff values detects clonal infiltration equivalent to about >20% by FISH, but that calling of minor sub clones is also feasible [4]. Thirty percent of patients’ tumors with clonally detectable 1q gain at relapse had a detectable, potential minor sub-clonal gain(1q) at diagnosis and 50% of del(17p) relapse tumors had potential sub-clonal del(17p) at diagnosis (Supplementary Fig. 4). Progressive clonal expansion of 1q positive tumors was a feature of 17.5% gain(1q) cases, whereby gain at diagnosis evolved into tetraploidy of 1q (amp(1q)) at relapse. Two of 15 tumors with gain of MYC at diagnosis progressed to amplification at relapse. This was also a feature with gain of 15q (4.4%) and 19p (2.3%), albeit at low frequency. We and others have demonstrated that patients with double or triple hit tumors (i.e., 2+ high-risk aberrations t(4;14), t(14;16), t(14;20), gain(1q), or del(17p)) have an especially poor prognosis [4]. It was noteworthy that some tumors with 0 or 1 lesions progressed to carrying double, triple and quadruple hits at relapse (Fig. 2). Amplification 1q has recently been proposed as an additional independent marker of high risk by some researchers [22]. In our study around two thirds of amp(1q) tumors were “double hit”, i.e., also carried t(4;14), t(14;16), t(14;20), or del(17p). Of all 178 relapsed tumors, nearly 10% carried both amp(1q) and “double hit” genetic features (Fig. 2).Fig. 2 Positive selection of co-occurrence of high-risk lesions. A Frequency bar chart of tumors characterized by number of high-risk markers, ranging from no (0) high-risk marker to co-occurrence of 4 markers. B Upset plots of Presentation (left) and Relapse (right) tumors, each showing frequency of individual high-risk lesions (left), type of combination of lesions (center lines with dots indicating presence of individual lesion) and frequency of specific combination of markers (top). C Bar chart showing the overall frequency of amp(1q) between presentation and relapse (overall bar height) and proportion of amp(1q) tumors showing 1q as the only high-risk aberration (single hit), or in combination with one or more other high-risk markers (double hit to quadruple hit). Impact of subtype on copy number profile Given the biological heterogeneity of MM we examined the relationship between CNAs and disease progression by subtype: those with IG translocations (t(4;14), t(11;14), t(14;16)/t(14;20)), and those with HRD, sub-grouped into those with and without gain of 11, in analogy to Translocation and Cyclin D (TC) classification (Supplementary Table 2) [4, 5]. Emerging CNA patterns at relapse were classified as branching (45.5% of all tumors), linear (22.5%), linear loss (19.1%), and stable (12.9%) (Fig. 3). In HRD the majority of tumors showed evidence of branching evolution (57.3%) (Fig. 3). In contrast, linear evolution dominated (36.8%) t(4;14) MM. t(11;14) tumors primarily showed either no CNA change at relapse (stable; 33.3%), or linear evolution (28.6%) (Fig. 3). Importantly, there was no relationship between acquisition of CNAs and either HDMEL or lenalidomide maintenance therapy (Fig. 4).Fig. 3 Relationship between CNAs at presentation and relapse and MM subtype. A Co-occurrence in evolution of novel CNAs at relapse in context of pathogenetic lesions (legend left side; dark bar = present, gray = absent; legend bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position) displayed in a heat map with unsupervised clustering for evolving CNAs. B Frequency of evolutionary patterns across all tumors. C Frequency of evolutionary patterns per major molecular MM subgroups. Fig. 4 Evolutionary patterns in context of trial treatment. A Comparison of frequencies of evolutionary patterns between transplant eligible (TE; younger, fitter patients) and transplant non eligible (TNE). B Comparison of frequencies of evolutionary patterns for patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR) (C) Heatmaps of CNA changes at relapse for tumors from patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR). For each group separately unsupervised clustering on CNA changes was performed and a dendrogram is shown on the left of each heat map. Legend on left side provides context on molecular background lesions (dark bar = present, gray = absent). Legend at bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position. Both del(13) (94.7%) and gain/amp (1q) (68.4%) were seen at high frequency in t(4;14) MM at presentation, and the CNAs were seen at even higher frequencies in relapse tumors at 100% and 79.0%, respectively (Supplementary Fig. 5). Moreover, at relapse del(17p) was a feature of 31.6% of t(4;14) tumors (Supplementary Fig. 5). In contrast, acquisition of 1q, 2p, 8q, 9p, 9q, or 6q CNAs, the changes occurring in t(11;14), were not common; each of these aberration was acquired in <5% of t(11;14) relapsed tumors (Fig. 3). Due to their low frequency, as expected, t(14;16) (two patients) and t(14;20) (one patient) tumors are not discussed; sequential CNA analysis providing limited information regarding subgroup evolutionary trajectory. Baseline and relapse CNAs for t(14;16) and t(14;20) shown in Supplementary Fig. 6. Finally, we examined the relationship between CNA change and MM subtypes defined by CCND expression; CCND1 (D1), CCND2 (D2), or both (D1 + D2) (Supplementary Fig. 7). Acquisition of del(17p) was associated primarily with D2 subtype (Supplementary Fig. 8). Specifically, acquired del(17p) at relapse was a feature of 14.6% of D2, 12.0% of D1 + 2, and 5.1% of D1 tumors. Overall, acquisition of new lesions was less frequent in HRD with gain(11), characterized by D1 expression, vs. other HRD tumors (Supplementary Fig. 9). Associations with patient outcome Gain(1q) (HR = 2.23; P < 0.001), del(1p)/CDKN2C (HR = 1.81; P = 0.046), gain(8q)/MYC (HR = 1.87; P = 0.033), and del(17p) (HR = 2.95; P < 0.001) considered as time dependent variables, i.e., including their acquisition at relapse, were all independently associated with shorter OS (Table 1; Supplementary Fig. 10; Supplementary Table 4).Table 1 Multivariate Cox regression analysis of risk factors for OS, where CNAs represent time dependent covariates. HR 95% CI P value t(4;14) 1.25 (0.62–2.54) 0.53 t(14;16) 1.75 (0.66–4.60) 0.26 Gain(1q) 2.23 (1.39–3.57) 0.0008 Del(1p)/CDKN2C 1.81 (1.01–2.26) 0.046 Gain(8q)/MYC 1.87 (1.05–3.31) 0.033 Del(17p) 2.95 (1.67–5.20) 0.0001 TNE 2.30 (1.41–3.75) 0.0008 HR hazard ratio, 95% CI 95% confidence interval. CNAs were stratified by time point of acquisition, i.e., “Gain-Gain” for those with stable gain and “Diploid-Gain” for those with evolution of gain(1q) at relapse. Gain(1q) from presentation and evolution of new gain(1q) at relapse were both associated with significantly shorter OS compared to normal 1q copy number (HR 2.11; P = 0.0040 and HR 2.00; P = 0.021, respectively). Median OS was 44.3 vs. 47.9 vs. 67.1 months for gain(1q) at diagnosis, new gain(1q) at relapse and normal 1q copy number at both time points, respectively (log-rank P = 0.007) (Fig. 5).Fig. 5 Relationship between emerging CNAs, evolutionary trajectories, and patient outcome. A Kaplan–Meier plot for overall survival in context of presence of CNAs for 1q. Equivalent plots for aberrations of (B) deletion of 1p21 (CDKN2C) (C) gain of 8q21 (MYC) (D) deletion of 17p (TP53) (E) evolutionary pattern. As per individual color-coded label for A–D, curves represent patients with tumors remaining diploid at both time points, changing from diploid to abnormal or showing abnormality at both time points. Acquired del(17p), del(1p/CDKN2C) or gain(8q/MYC) at relapse were not clearly associated with a significantly worse OS in subgroup analyses, although our power to demonstrate a relationship was naturally limited by low frequency of these CNAs. Median OS was 31.3 vs. 60.5 vs. 65.4 months for del(17p) at diagnosis, emergence at relapse and absence at both, respectively (log-rank P < 0.001) (Fig. 5). Median OS was 38.3 vs. 44.6 vs. 63.4 months for del(1p/CDKN2C) at diagnosis, emergence at relapse or absence, respectively (log-rank P = 0.03) (Fig. 5); and for gain(8q/MYC), 38.3 vs. 36.2 vs. 63.4 months, respectively (log-rank P = 0.07) (Fig. 5). Of interest, type of evolutionary pattern was associated with OS; branching evolution was significantly associated with the shortest and linear loss with the longest OS (HR 2.61, P = 0.0048), with median OS being 44.6 vs. 59.6 vs. 62.0 vs. 68.1 months for branching, linear, no change and linear loss respectively (log-rank P = 0.02) (Fig. 5). Discussion Our analysis demonstrates that progression of MM is characterized by emergence of clones with additional large-scale chromosomal changes, commonly involving 1q. Gain or amp(1q) frequently co-evolves with other CNAs, either implicating 1q directly in their genesis as per “jumping 1q” hypothesis, or highlighting 1q as a region providing clonal advantage for genetically instable tumors [23]. While a number of genes on 1q have been proposed as drivers, our study does not provide data to make a specific inference [8, 24–27]. Our findings also suggest progression of MM is associated with positive selection of sub-chromosomal loss of 1p, implicating CDKN2C, and thereby indirectly CDK4/6 in conferring clonal survival benefit at progression. We also identified recurrent sub-chromosomal gain at relapse of an area to which MYC maps (chr8q24.21), in line with its driver role in B-cell malignancies [28, 29]. By considering MM molecular subtype, we highlight differences in evolution trajectories, particularly between HRD and IG translocated MM, but also between t(4;14) and t(11;14) and/or between CCND2 and CCND1 driven tumors [5]. Of note, there is a marked enrichment of acquisition of del(17p) at relapse in CCND2 driven tumors which has, to our knowledge, not been described before. These differences are features of subtypes irrespective of therapy. Our findings are in keeping with published observations for evolution of pre-therapeutic mutational patterns but extend these in context of therapy and relapse [30–32]. We also describe, to our knowledge for the first time, an association between CNA evolution pattern and subsequent outcome. Whether individual CNA evolution pattern has independent clinical relevance and could be included in management considerations at relapse requires further investigation. We identified only a low frequency of CNAs to which IMiD response genes map. In conjuncture with published somatic SNV data, results suggest mutation of these genes per se is not the major determinant of acquired resistance to lenalidomide, or other members of this class of agent in MM [12, 14–16, 33–35]. We demonstrate, to our knowledge for the first time, in a randomized controlled trial that acquisition of gain(1q) at relapse is independently and strongly associated with inferior OS [36]. Although findings are also indicative for del(17p), del(1p/CDKN2C) and gain(8q/MYC), our power to robustly assert clinical relevance of acquired lesions at relapse is inevitably limited by the lower frequency of these CNAs [37]. Clinical evaluation of these markers at relapse is technically feasible in most developed healthcare systems, but currently not widely recommended [38–40]. It is unknown whether sub-clones residing outside of the standard iliac crest bone marrow sampling area at diagnosis are the main source of clonal evolution detected at relapse or whether these predominantly emerge through ongoing genomic instability [12]. Multi-region bone sampling in MM is associated with significant risk and morbidity, making its implementation as part of standard care very challenging. Functional bone marrow soft tissue imaging techniques such as diffusion-weighted whole body MRI and/or molecular techniques including circulating tumor DNA profiling are promising methods in development which may contribute to diagnostic assessment of spatial MM heterogeneity in the future. However, sensitivity, precision and clinical relevance of minor sub-clone detection from a single time point for these methods remains to be established, in particular if results differ from those of parallel bone marrow sampling, before informing clinical management [41–44]. All patients received uniform trial treatment, in particular providing insight into thalidomide and lenalidomide associated CNA changes. However, patients also received low-doses of the oral alkylator cyclophosphamide during induction, which may have specific impact on CNA changes, potentially limiting generalizability of our findings. In addition, molecular information generated with a targeted tool like digitalMLPA is inherently focused and does not discriminate complex processes potentially underlying identified CNAs, such as chromotripsis or chromoplexy, which are detectable by discovery tools such as whole genome sequencing, or single nucleotide variants captured by myeloma specific CNA/sequencing panels [29, 45–47]. Our data also cannot reflect accompanying changes of the tumor microenvironment, which have been implicated in myeloma progression [48]. However, digitalMLPA is in development for clinical diagnostic application, offers sensitive CNA information specific to myeloma from low tumor DNA quantities at high throughput. It requires limited computational infrastructure and uses standardized analysis algorithms, thus overcoming the significant limitations of conventional FISH analysis [20]. As our study demonstrates, digitalMLPA is suitable for longitudinal intra-individual tracking and provides a standardized and accessible method for cross-study validation and putative implementation in molecularly stratified prospective clinical trials. Genetic re-profiling at relapse in MM is currently not widely recommended and, as a consequence, often not reimbursed [10, 39, 49]. Whilst treatment options for relapsed disease were until recently very limited, a range of therapeutic regimens with varying intensity are now approved and available, requiring better tools for clinical decision making at relapse [50–53]. Adapting first-line therapy and its intensity to individual tumor risk markers in MM is now a key focus of research, with multiple genetically stratified prospective clinical trials currently ongoing [10, 54, 55]. The debate about optimal tailoring of second line treatment is likely to intensify with increasing therapeutic options. Our study demonstrates not only the frequency of emerging high-risk CNAs at MM relapse, but also the unmet clinical need of patients with chromosomally evolving MM. These patients should ideally be recognized early during relapse and prospective clinical trials investigating longitudinal management strategies adapted to dynamic risk profiling, designed [56]. Our findings strongly support repeated tumor molecular analysis in MM in context of modern treatment, even in circumstances where only selected markers such as 1q can be tested, as a means of tailoring patient treatment beyond first-line therapy. Supplementary information Supplementary Methods Supplementary Tables Supplementary Figures Supplementary information The online version of this article (10.1038/s41375-020-01096-y) contains supplementary material, which is available to authorized users. Acknowledgements This work was supported by research grants from Celgene, Myeloma UK and the National Institute of Health Biomedical Research Center at the Royal Marsden Hospital and Institute of Cancer Research, London. MFK was supported by a Jacquelin Forbes-Nixon Fellowship. Primary financial support for NCRI Myeloma XI was provided by Cancer Research UK (C1298/A10410). Unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, Ortho Biotech, Amgen, and Merck Sharp & Dohme supported trial coordination. We are grateful for the support of the Clinical Trials Research Unit (CTRU) at Leeds, to the NCRI Haemato-oncology subgroup, investigators and patients. The Myeloma XI trial was conducted with support of the NCRI Hematological Oncology Clinical Studies Group. Author contributions Conception and design: JC, RSH, and MFK. Acquisition of data: all authors. Analysis of data: JC, MFK. Paper writing: JC, RSH, and MFK. Compliance with ethical standards Conflict of interest MWJ: Janssen—consultancy, honoraria, travel support, research funding; Takeda—consultancy, honoraria, travel support; Amgen—consultancy, honoraria, travel support; Celgene Corporation—consultancy, honoraria, research funding; Novartis—consultancy, honoraria. MTD: Abingdon Health—equity ownership, membership on an entity’s board of directors or advisory committees. RGO: Takeda—honoraria, travel support; Janssen—consultancy, travel support; Celgene Corporation—consultancy, honoraria, research funding. JL: Janssen—consultancy; Novartis—travel support; Takeda—honoraria, travel support; Bristol-Myers Squibb—consultancy, travel support; Celgene Corporation—consultancy, honoraria, travel support. KK: Celgene Corporation—travel support, research funding; Janssen—travel support, research funding. WMG: Celgene Corporation—consultancy, research funding; Amgen, Merck Sharp and Dohme—research funding; Janssen—honoraria. FED: Amgen—consultancy, honoraria; AbbVie—consultancy, honoraria; Takeda—consultancy, honoraria; Janssen—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria. GJM: Janssen—research funding; Bristol-Myers Squibb—consultancy, honoraria; Takeda—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria; Amgen—consultancy, honoraria; GSK—consultancy, honoraria; Karyopharm—consultancy, honoraria. GC: Takeda—consultancy, honoraria, research funding, speakers bureau; Glycomimetics—consultancy, honoraria; Sanofi—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, research funding, speakers bureau; Janssen—consultancy, honoraria, research funding, speakers bureau; Bristol-Myers Squibb—consultancy, honoraria; Amgen—consultancy, honoraria, research funding, speakers bureau. LA: MRC-Holland—employment. SS: MRC-Holland—employment. DAC: Celgene Corporation, Amgen, Merck Sharp and Dohme—research funding. GHJ: Roche—consultancy, honoraria, speakers bureau; Amgen—consultancy, honoraria, speakers bureau; Janssen—consultancy, honoraria, speakers bureau; Merck Sharp and Dohme—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, travel support, research funding, speakers bureau; Takeda—consultancy, honoraria, travel support, research funding, speakers bureau. MFK: AbbVie—consultancy; Bristol-Myers Squibb—consultancy, travel support; Chugai—consultancy; GSK—consultancy; Janssen—consultancy, honoraria, research funding; Amgen—consultancy, honoraria; Takeda—consultancy, travel support; Celgene Corporation—consultancy, honoraria, and research funding. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	CARFILZOMIB, CYCLOPHOSPHAMIDE, DEXAMETHASONE	DrugsGivenReaction	CC BY	33262523	20,436,778	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'.	Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial. Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse. Introduction Multiple myeloma (MM) is caused by the malignant clonal expansion of plasma cells in the bone marrow [1]. Approximately 40% of MM tumors harbor chromosome t(4;14), t(11;14), or t(14;16)/t(14;20) translocations, which result in overexpression of oncogenes (including WHSC1/MMSET/NSD2, FGFR3, CCND1, MAF, and MAFB) through juxtaposition to the immunoglobulin heavy-chain locus [2, 3]. Other MM tumors exhibit hyperdiploidy (HRD), which is considered an alternative initiating event. Increased expression of CCND1 in t(11;14) and HRD and increased CCND2 expression in t(4;14), t(14;16)/t(14;20), and HRD are unifying downstream consequences of initiating lesions [4–10]. Recent next-generation sequencing projects have provided insight into the sub-clonal complexity of tumor progression in MM [11–14]. However, few recurrent single nucleotide changes have been reported to be associated with disease relapse, notably sub-clonal mutations of cereblon in immunomodulatory drug (IMiD) treated patients. Knowledge about their prognostic impact remains limited [15]. In contrast, several large-scale chromosomal abnormalities, including gain(1q), del(1p), and del(17p) have been shown to be acquired during tumor progression, but their association with tumor subtype, treatment and outcome is not well understood [11, 16]. Recent studies of the relationship between copy number aberrations (CNAs) and progression of MM have largely been based on short-read sequencing or FISH. Importantly, few studies have been performed on patients from a randomized clinical trial and the impact of therapy on acquisition of CNAs remains unclear [15, 16]. To gain insight into the relationship between CNAs and progression of MM we performed virtual karyotyping of all chromosomes and targeted hotspot profiling using digital multiplexed ligation-dependent probe amplification (digitalMLPA) in matched diagnosis–relapse tumor pairs in 178 UK NCRI Myeloma XI trial patients [17]. We show that acquisition of CNAs is strongly correlated with MM subgroups. Additionally, a number of acquired changes have independent predictive value for defining patient outcome. Material and methods Patients We studied 178 newly diagnosed MM patients enrolled in UK NCRI Myeloma XI (ISRCTN49407852) for which high quality bone marrow tumor material at both presentation and relapse was available. First outcomes of the trial have been published recently [17]. Briefly, patients were initially randomized to triplet induction with thalidomide (CTD), lenalidomide (CRD), or carfilzomib and lenalidomide (KCRD; transplant-eligible patients only) in combination with cyclophosphamide and dexamethasone. Insufficient responders (partial or minimal response) were randomized to cyclophosphamide, bortezomib and dexamethasone (CVD) vs. no intensification and nonresponders (stable or progressive disease) received CVD. Younger, fitter patients received high-dose melphalan (HDMEL) and autologous stem-cell transplantation, patients were randomized to receive lenalidomide, lenalidomide plus vorinostat, or observation. Maintenance treatment continued until progressive disease in the absence of toxicity (Supplementary Fig. 1). Median time to progression was 20.7 months (range 3.7–71.9 months) and median follow-up 47.0 months. Baseline characteristics are summarized in Supplementary Table 1. The frequency of chromosomal aberrations detectable in the 178 patients at presentation were representative of the overall trial cohort (Supplementary Table 2) [4]. For all patients CD138-positive tumor cells were immunomagnetically selected at presentation and relapse and quality controlled for tumor cell purity (>95%), DNA and RNA were extracted using QIAGEN (Hilden, Germany) Allprep kits. Additional molecular quality control including longitudinal consistency for IgD deletion status was performed for all cases. Matched identity of presentation-relapse pairs was confirmed using single nucleotide and/or insertion/deletion polymorphisms assayed by digitalMLPA D006-X2 for all samples. All patients provided written informed consent. The study was approved by the UK National Research Ethics Service, research ethics committees at participating centers and the UK Medicines and Healthcare Products Regulatory Agency. Translocation and copy number profiling Multiplexed qRT-PCR was used to determine t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20) status in tumors, based on the translocation cyclin D (TC) classification system as previously described [5, 18]. Targeted genome wide CNA status at presentation and relapse in each patient was assessed with a newly developed research version of D006-X2 Multiple Myeloma digitalMLPA probemix, as previously described (Supplementary Methods) [19, 20]. Details of each probe and their respective genomic positions are provided in Supplementary Table 3. CNAs involving sex chromosomes were not considered. CNAs were called if ≥50% of probes mapping to an individual gene or genomic region deviated from normal diploid pattern. Statistical analyses Analyses were performed in R version 3.5.2 using “dplyr”, “tidyr”, “stats”, “survival” and “survminer”, “ComplexHeatmap” and “ggpubr” packages. The association between categorical variables was examined using Fishers exact test and between continuous variables using the Wilcoxon signed-rank test. Progression-free survival (PFS) was defined as time from induction randomization to progression, according to International Myeloma Working Group criteria, or death of any cause. Overall survival (OS) was time from induction randomization to death of any cause. Cox proportional hazards (PH) regression was used to estimate univariate and multivariable hazard ratios (HRs) and 95% confidence intervals (CI). To examine the predictive value of evolution in CNA status for subsequent therapy, high-risk CNA were considered as time dependent covariates within the multivariate model. The PH assumption was tested to investigate whether time dependent covariate effects persisted irrespective of time of acquisition (Supplementary Methods). Multivariate covariates included t(4;14), t(14;16), del(1p), gain(1q), del(17p) and treatment pathway (transplant eligible vs. not). This is relevant because, although the median follow-up of this cohort is long, the inherent requirement of a relapse biopsy excludes the longest responders from our analyses as they are still on active trial medication or observation with no evidence of disease progression. Differences between Kaplan–Meier survival curves was assessed using the log-rank test. A two-sided P value of ≤0.05 was considered statistically significant. Results Acquisition of new CNAs is a feature of relapse Relapse was associated with the acquisition of new CNAs in 87.1% of tumors, most (73.2%) being large-scale chromosome changes. Across all patients, relapse was associated with a higher number of CNAs: median 11.5 (range 0–34) vs. median 12 (range 0–29) (P = 0.0058). As previously well-documented [16, 21], IGH translocations were clonal at presentation and their status did not change at relapse. The most frequent chromosomal changes associated with relapse were gain or amplification of 1q (19%), del(13q) (10%), gain or amplification of 11q (9%) and del(17p)/TP53 in (8%) (Fig. 1; Supplementary Table 2). Although not common, some clonal CNAs detectable at presentation were not detectable at relapse, in particular gain of odd numbered chromosomes in HRD tumors (Supplementary Fig. 2).Fig. 1 Recurrent chromosomal and sub-chromosomal CNA changes at relapse. A Frequency of CNAs emerging at relapse affecting chromosome arms, including new gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green) plotted as a bar graph. B Bar graph showing frequency of 1q, 13q, and 17p CNAs, including gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green), at presentation and relapse. C Heat map of evolving chromosome 1 CNAs at relapse, 63 tumors with change in this region at relapse. On the left (Y-axis) dendrogram representing unsupervised clustering analysis of emerging CNAs in areas interrogated by digitalMLPA probes, which are annotated with gene names and chromosomal location below (X-axis). Change per probe and tumor color-coded as per scale representing normalized digitalMLPA copy number ratios with 1.0 equivalent to normal/diploid. Evolution of sub-chromosomal aberrations In contrast to 1q gain, which generally involved the whole chromosomal arm, clonal 1p deletions tended to be sub-chromosomal (Fig. 1): 1p32.3 deletion (9/178; 5.1%) implicating CDKN2C or 1p12 implicating FAM46C (4/178; 2.2%). In nine of 22 tumors with 1p12 (FAM46C) deletion at diagnosis, the deletion was not clonally detectable at relapse; in contrast all but one of the 8 presentation 1p32.3 (CDKN2C) deletions were detectable at relapse. Focal gain at relapse also affected 8q24.21, involving the MYC locus, in 10/178 (5.6%) tumors. In three of 15 tumors with MYC gain at presentation, reversion to diploid status was a feature of relapse. Sub-chromosomal CNAs involving IMiD response genes—CRBN (3p26.2), IKZF1 (7p12.2), IKZF3 (17q12), and IRF4 (6p25.3)—were infrequent (Supplementary Fig. 3). Most were detectable in tumors relapsing off therapy (no maintenance); only 2 out of 10 were a feature of tumors from patients in receipt of lenalidomide maintenance (1 deletion of CRBN; 1 gain IRF4). Evolution of driver copy number aberrations We next examined for clonal emergence at relapse of sub-clonal changes at diagnosis, focusing on the most frequent drivers—gain(1q) and del(17p). We and others showed before that calling of CNAs using conservative high confidence MLPA cutoff values detects clonal infiltration equivalent to about >20% by FISH, but that calling of minor sub clones is also feasible [4]. Thirty percent of patients’ tumors with clonally detectable 1q gain at relapse had a detectable, potential minor sub-clonal gain(1q) at diagnosis and 50% of del(17p) relapse tumors had potential sub-clonal del(17p) at diagnosis (Supplementary Fig. 4). Progressive clonal expansion of 1q positive tumors was a feature of 17.5% gain(1q) cases, whereby gain at diagnosis evolved into tetraploidy of 1q (amp(1q)) at relapse. Two of 15 tumors with gain of MYC at diagnosis progressed to amplification at relapse. This was also a feature with gain of 15q (4.4%) and 19p (2.3%), albeit at low frequency. We and others have demonstrated that patients with double or triple hit tumors (i.e., 2+ high-risk aberrations t(4;14), t(14;16), t(14;20), gain(1q), or del(17p)) have an especially poor prognosis [4]. It was noteworthy that some tumors with 0 or 1 lesions progressed to carrying double, triple and quadruple hits at relapse (Fig. 2). Amplification 1q has recently been proposed as an additional independent marker of high risk by some researchers [22]. In our study around two thirds of amp(1q) tumors were “double hit”, i.e., also carried t(4;14), t(14;16), t(14;20), or del(17p). Of all 178 relapsed tumors, nearly 10% carried both amp(1q) and “double hit” genetic features (Fig. 2).Fig. 2 Positive selection of co-occurrence of high-risk lesions. A Frequency bar chart of tumors characterized by number of high-risk markers, ranging from no (0) high-risk marker to co-occurrence of 4 markers. B Upset plots of Presentation (left) and Relapse (right) tumors, each showing frequency of individual high-risk lesions (left), type of combination of lesions (center lines with dots indicating presence of individual lesion) and frequency of specific combination of markers (top). C Bar chart showing the overall frequency of amp(1q) between presentation and relapse (overall bar height) and proportion of amp(1q) tumors showing 1q as the only high-risk aberration (single hit), or in combination with one or more other high-risk markers (double hit to quadruple hit). Impact of subtype on copy number profile Given the biological heterogeneity of MM we examined the relationship between CNAs and disease progression by subtype: those with IG translocations (t(4;14), t(11;14), t(14;16)/t(14;20)), and those with HRD, sub-grouped into those with and without gain of 11, in analogy to Translocation and Cyclin D (TC) classification (Supplementary Table 2) [4, 5]. Emerging CNA patterns at relapse were classified as branching (45.5% of all tumors), linear (22.5%), linear loss (19.1%), and stable (12.9%) (Fig. 3). In HRD the majority of tumors showed evidence of branching evolution (57.3%) (Fig. 3). In contrast, linear evolution dominated (36.8%) t(4;14) MM. t(11;14) tumors primarily showed either no CNA change at relapse (stable; 33.3%), or linear evolution (28.6%) (Fig. 3). Importantly, there was no relationship between acquisition of CNAs and either HDMEL or lenalidomide maintenance therapy (Fig. 4).Fig. 3 Relationship between CNAs at presentation and relapse and MM subtype. A Co-occurrence in evolution of novel CNAs at relapse in context of pathogenetic lesions (legend left side; dark bar = present, gray = absent; legend bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position) displayed in a heat map with unsupervised clustering for evolving CNAs. B Frequency of evolutionary patterns across all tumors. C Frequency of evolutionary patterns per major molecular MM subgroups. Fig. 4 Evolutionary patterns in context of trial treatment. A Comparison of frequencies of evolutionary patterns between transplant eligible (TE; younger, fitter patients) and transplant non eligible (TNE). B Comparison of frequencies of evolutionary patterns for patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR) (C) Heatmaps of CNA changes at relapse for tumors from patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR). For each group separately unsupervised clustering on CNA changes was performed and a dendrogram is shown on the left of each heat map. Legend on left side provides context on molecular background lesions (dark bar = present, gray = absent). Legend at bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position. Both del(13) (94.7%) and gain/amp (1q) (68.4%) were seen at high frequency in t(4;14) MM at presentation, and the CNAs were seen at even higher frequencies in relapse tumors at 100% and 79.0%, respectively (Supplementary Fig. 5). Moreover, at relapse del(17p) was a feature of 31.6% of t(4;14) tumors (Supplementary Fig. 5). In contrast, acquisition of 1q, 2p, 8q, 9p, 9q, or 6q CNAs, the changes occurring in t(11;14), were not common; each of these aberration was acquired in <5% of t(11;14) relapsed tumors (Fig. 3). Due to their low frequency, as expected, t(14;16) (two patients) and t(14;20) (one patient) tumors are not discussed; sequential CNA analysis providing limited information regarding subgroup evolutionary trajectory. Baseline and relapse CNAs for t(14;16) and t(14;20) shown in Supplementary Fig. 6. Finally, we examined the relationship between CNA change and MM subtypes defined by CCND expression; CCND1 (D1), CCND2 (D2), or both (D1 + D2) (Supplementary Fig. 7). Acquisition of del(17p) was associated primarily with D2 subtype (Supplementary Fig. 8). Specifically, acquired del(17p) at relapse was a feature of 14.6% of D2, 12.0% of D1 + 2, and 5.1% of D1 tumors. Overall, acquisition of new lesions was less frequent in HRD with gain(11), characterized by D1 expression, vs. other HRD tumors (Supplementary Fig. 9). Associations with patient outcome Gain(1q) (HR = 2.23; P < 0.001), del(1p)/CDKN2C (HR = 1.81; P = 0.046), gain(8q)/MYC (HR = 1.87; P = 0.033), and del(17p) (HR = 2.95; P < 0.001) considered as time dependent variables, i.e., including their acquisition at relapse, were all independently associated with shorter OS (Table 1; Supplementary Fig. 10; Supplementary Table 4).Table 1 Multivariate Cox regression analysis of risk factors for OS, where CNAs represent time dependent covariates. HR 95% CI P value t(4;14) 1.25 (0.62–2.54) 0.53 t(14;16) 1.75 (0.66–4.60) 0.26 Gain(1q) 2.23 (1.39–3.57) 0.0008 Del(1p)/CDKN2C 1.81 (1.01–2.26) 0.046 Gain(8q)/MYC 1.87 (1.05–3.31) 0.033 Del(17p) 2.95 (1.67–5.20) 0.0001 TNE 2.30 (1.41–3.75) 0.0008 HR hazard ratio, 95% CI 95% confidence interval. CNAs were stratified by time point of acquisition, i.e., “Gain-Gain” for those with stable gain and “Diploid-Gain” for those with evolution of gain(1q) at relapse. Gain(1q) from presentation and evolution of new gain(1q) at relapse were both associated with significantly shorter OS compared to normal 1q copy number (HR 2.11; P = 0.0040 and HR 2.00; P = 0.021, respectively). Median OS was 44.3 vs. 47.9 vs. 67.1 months for gain(1q) at diagnosis, new gain(1q) at relapse and normal 1q copy number at both time points, respectively (log-rank P = 0.007) (Fig. 5).Fig. 5 Relationship between emerging CNAs, evolutionary trajectories, and patient outcome. A Kaplan–Meier plot for overall survival in context of presence of CNAs for 1q. Equivalent plots for aberrations of (B) deletion of 1p21 (CDKN2C) (C) gain of 8q21 (MYC) (D) deletion of 17p (TP53) (E) evolutionary pattern. As per individual color-coded label for A–D, curves represent patients with tumors remaining diploid at both time points, changing from diploid to abnormal or showing abnormality at both time points. Acquired del(17p), del(1p/CDKN2C) or gain(8q/MYC) at relapse were not clearly associated with a significantly worse OS in subgroup analyses, although our power to demonstrate a relationship was naturally limited by low frequency of these CNAs. Median OS was 31.3 vs. 60.5 vs. 65.4 months for del(17p) at diagnosis, emergence at relapse and absence at both, respectively (log-rank P < 0.001) (Fig. 5). Median OS was 38.3 vs. 44.6 vs. 63.4 months for del(1p/CDKN2C) at diagnosis, emergence at relapse or absence, respectively (log-rank P = 0.03) (Fig. 5); and for gain(8q/MYC), 38.3 vs. 36.2 vs. 63.4 months, respectively (log-rank P = 0.07) (Fig. 5). Of interest, type of evolutionary pattern was associated with OS; branching evolution was significantly associated with the shortest and linear loss with the longest OS (HR 2.61, P = 0.0048), with median OS being 44.6 vs. 59.6 vs. 62.0 vs. 68.1 months for branching, linear, no change and linear loss respectively (log-rank P = 0.02) (Fig. 5). Discussion Our analysis demonstrates that progression of MM is characterized by emergence of clones with additional large-scale chromosomal changes, commonly involving 1q. Gain or amp(1q) frequently co-evolves with other CNAs, either implicating 1q directly in their genesis as per “jumping 1q” hypothesis, or highlighting 1q as a region providing clonal advantage for genetically instable tumors [23]. While a number of genes on 1q have been proposed as drivers, our study does not provide data to make a specific inference [8, 24–27]. Our findings also suggest progression of MM is associated with positive selection of sub-chromosomal loss of 1p, implicating CDKN2C, and thereby indirectly CDK4/6 in conferring clonal survival benefit at progression. We also identified recurrent sub-chromosomal gain at relapse of an area to which MYC maps (chr8q24.21), in line with its driver role in B-cell malignancies [28, 29]. By considering MM molecular subtype, we highlight differences in evolution trajectories, particularly between HRD and IG translocated MM, but also between t(4;14) and t(11;14) and/or between CCND2 and CCND1 driven tumors [5]. Of note, there is a marked enrichment of acquisition of del(17p) at relapse in CCND2 driven tumors which has, to our knowledge, not been described before. These differences are features of subtypes irrespective of therapy. Our findings are in keeping with published observations for evolution of pre-therapeutic mutational patterns but extend these in context of therapy and relapse [30–32]. We also describe, to our knowledge for the first time, an association between CNA evolution pattern and subsequent outcome. Whether individual CNA evolution pattern has independent clinical relevance and could be included in management considerations at relapse requires further investigation. We identified only a low frequency of CNAs to which IMiD response genes map. In conjuncture with published somatic SNV data, results suggest mutation of these genes per se is not the major determinant of acquired resistance to lenalidomide, or other members of this class of agent in MM [12, 14–16, 33–35]. We demonstrate, to our knowledge for the first time, in a randomized controlled trial that acquisition of gain(1q) at relapse is independently and strongly associated with inferior OS [36]. Although findings are also indicative for del(17p), del(1p/CDKN2C) and gain(8q/MYC), our power to robustly assert clinical relevance of acquired lesions at relapse is inevitably limited by the lower frequency of these CNAs [37]. Clinical evaluation of these markers at relapse is technically feasible in most developed healthcare systems, but currently not widely recommended [38–40]. It is unknown whether sub-clones residing outside of the standard iliac crest bone marrow sampling area at diagnosis are the main source of clonal evolution detected at relapse or whether these predominantly emerge through ongoing genomic instability [12]. Multi-region bone sampling in MM is associated with significant risk and morbidity, making its implementation as part of standard care very challenging. Functional bone marrow soft tissue imaging techniques such as diffusion-weighted whole body MRI and/or molecular techniques including circulating tumor DNA profiling are promising methods in development which may contribute to diagnostic assessment of spatial MM heterogeneity in the future. However, sensitivity, precision and clinical relevance of minor sub-clone detection from a single time point for these methods remains to be established, in particular if results differ from those of parallel bone marrow sampling, before informing clinical management [41–44]. All patients received uniform trial treatment, in particular providing insight into thalidomide and lenalidomide associated CNA changes. However, patients also received low-doses of the oral alkylator cyclophosphamide during induction, which may have specific impact on CNA changes, potentially limiting generalizability of our findings. In addition, molecular information generated with a targeted tool like digitalMLPA is inherently focused and does not discriminate complex processes potentially underlying identified CNAs, such as chromotripsis or chromoplexy, which are detectable by discovery tools such as whole genome sequencing, or single nucleotide variants captured by myeloma specific CNA/sequencing panels [29, 45–47]. Our data also cannot reflect accompanying changes of the tumor microenvironment, which have been implicated in myeloma progression [48]. However, digitalMLPA is in development for clinical diagnostic application, offers sensitive CNA information specific to myeloma from low tumor DNA quantities at high throughput. It requires limited computational infrastructure and uses standardized analysis algorithms, thus overcoming the significant limitations of conventional FISH analysis [20]. As our study demonstrates, digitalMLPA is suitable for longitudinal intra-individual tracking and provides a standardized and accessible method for cross-study validation and putative implementation in molecularly stratified prospective clinical trials. Genetic re-profiling at relapse in MM is currently not widely recommended and, as a consequence, often not reimbursed [10, 39, 49]. Whilst treatment options for relapsed disease were until recently very limited, a range of therapeutic regimens with varying intensity are now approved and available, requiring better tools for clinical decision making at relapse [50–53]. Adapting first-line therapy and its intensity to individual tumor risk markers in MM is now a key focus of research, with multiple genetically stratified prospective clinical trials currently ongoing [10, 54, 55]. The debate about optimal tailoring of second line treatment is likely to intensify with increasing therapeutic options. Our study demonstrates not only the frequency of emerging high-risk CNAs at MM relapse, but also the unmet clinical need of patients with chromosomally evolving MM. These patients should ideally be recognized early during relapse and prospective clinical trials investigating longitudinal management strategies adapted to dynamic risk profiling, designed [56]. Our findings strongly support repeated tumor molecular analysis in MM in context of modern treatment, even in circumstances where only selected markers such as 1q can be tested, as a means of tailoring patient treatment beyond first-line therapy. Supplementary information Supplementary Methods Supplementary Tables Supplementary Figures Supplementary information The online version of this article (10.1038/s41375-020-01096-y) contains supplementary material, which is available to authorized users. Acknowledgements This work was supported by research grants from Celgene, Myeloma UK and the National Institute of Health Biomedical Research Center at the Royal Marsden Hospital and Institute of Cancer Research, London. MFK was supported by a Jacquelin Forbes-Nixon Fellowship. Primary financial support for NCRI Myeloma XI was provided by Cancer Research UK (C1298/A10410). Unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, Ortho Biotech, Amgen, and Merck Sharp & Dohme supported trial coordination. We are grateful for the support of the Clinical Trials Research Unit (CTRU) at Leeds, to the NCRI Haemato-oncology subgroup, investigators and patients. The Myeloma XI trial was conducted with support of the NCRI Hematological Oncology Clinical Studies Group. Author contributions Conception and design: JC, RSH, and MFK. Acquisition of data: all authors. Analysis of data: JC, MFK. Paper writing: JC, RSH, and MFK. Compliance with ethical standards Conflict of interest MWJ: Janssen—consultancy, honoraria, travel support, research funding; Takeda—consultancy, honoraria, travel support; Amgen—consultancy, honoraria, travel support; Celgene Corporation—consultancy, honoraria, research funding; Novartis—consultancy, honoraria. MTD: Abingdon Health—equity ownership, membership on an entity’s board of directors or advisory committees. RGO: Takeda—honoraria, travel support; Janssen—consultancy, travel support; Celgene Corporation—consultancy, honoraria, research funding. JL: Janssen—consultancy; Novartis—travel support; Takeda—honoraria, travel support; Bristol-Myers Squibb—consultancy, travel support; Celgene Corporation—consultancy, honoraria, travel support. KK: Celgene Corporation—travel support, research funding; Janssen—travel support, research funding. WMG: Celgene Corporation—consultancy, research funding; Amgen, Merck Sharp and Dohme—research funding; Janssen—honoraria. FED: Amgen—consultancy, honoraria; AbbVie—consultancy, honoraria; Takeda—consultancy, honoraria; Janssen—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria. GJM: Janssen—research funding; Bristol-Myers Squibb—consultancy, honoraria; Takeda—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria; Amgen—consultancy, honoraria; GSK—consultancy, honoraria; Karyopharm—consultancy, honoraria. GC: Takeda—consultancy, honoraria, research funding, speakers bureau; Glycomimetics—consultancy, honoraria; Sanofi—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, research funding, speakers bureau; Janssen—consultancy, honoraria, research funding, speakers bureau; Bristol-Myers Squibb—consultancy, honoraria; Amgen—consultancy, honoraria, research funding, speakers bureau. LA: MRC-Holland—employment. SS: MRC-Holland—employment. DAC: Celgene Corporation, Amgen, Merck Sharp and Dohme—research funding. GHJ: Roche—consultancy, honoraria, speakers bureau; Amgen—consultancy, honoraria, speakers bureau; Janssen—consultancy, honoraria, speakers bureau; Merck Sharp and Dohme—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, travel support, research funding, speakers bureau; Takeda—consultancy, honoraria, travel support, research funding, speakers bureau. MFK: AbbVie—consultancy; Bristol-Myers Squibb—consultancy, travel support; Chugai—consultancy; GSK—consultancy; Janssen—consultancy, honoraria, research funding; Amgen—consultancy, honoraria; Takeda—consultancy, travel support; Celgene Corporation—consultancy, honoraria, and research funding. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	CARFILZOMIB, CYCLOPHOSPHAMIDE, DEXAMETHASONE	DrugsGivenReaction	CC BY	33262523	20,436,778	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Plasma cell myeloma'.	Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial. Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse. Introduction Multiple myeloma (MM) is caused by the malignant clonal expansion of plasma cells in the bone marrow [1]. Approximately 40% of MM tumors harbor chromosome t(4;14), t(11;14), or t(14;16)/t(14;20) translocations, which result in overexpression of oncogenes (including WHSC1/MMSET/NSD2, FGFR3, CCND1, MAF, and MAFB) through juxtaposition to the immunoglobulin heavy-chain locus [2, 3]. Other MM tumors exhibit hyperdiploidy (HRD), which is considered an alternative initiating event. Increased expression of CCND1 in t(11;14) and HRD and increased CCND2 expression in t(4;14), t(14;16)/t(14;20), and HRD are unifying downstream consequences of initiating lesions [4–10]. Recent next-generation sequencing projects have provided insight into the sub-clonal complexity of tumor progression in MM [11–14]. However, few recurrent single nucleotide changes have been reported to be associated with disease relapse, notably sub-clonal mutations of cereblon in immunomodulatory drug (IMiD) treated patients. Knowledge about their prognostic impact remains limited [15]. In contrast, several large-scale chromosomal abnormalities, including gain(1q), del(1p), and del(17p) have been shown to be acquired during tumor progression, but their association with tumor subtype, treatment and outcome is not well understood [11, 16]. Recent studies of the relationship between copy number aberrations (CNAs) and progression of MM have largely been based on short-read sequencing or FISH. Importantly, few studies have been performed on patients from a randomized clinical trial and the impact of therapy on acquisition of CNAs remains unclear [15, 16]. To gain insight into the relationship between CNAs and progression of MM we performed virtual karyotyping of all chromosomes and targeted hotspot profiling using digital multiplexed ligation-dependent probe amplification (digitalMLPA) in matched diagnosis–relapse tumor pairs in 178 UK NCRI Myeloma XI trial patients [17]. We show that acquisition of CNAs is strongly correlated with MM subgroups. Additionally, a number of acquired changes have independent predictive value for defining patient outcome. Material and methods Patients We studied 178 newly diagnosed MM patients enrolled in UK NCRI Myeloma XI (ISRCTN49407852) for which high quality bone marrow tumor material at both presentation and relapse was available. First outcomes of the trial have been published recently [17]. Briefly, patients were initially randomized to triplet induction with thalidomide (CTD), lenalidomide (CRD), or carfilzomib and lenalidomide (KCRD; transplant-eligible patients only) in combination with cyclophosphamide and dexamethasone. Insufficient responders (partial or minimal response) were randomized to cyclophosphamide, bortezomib and dexamethasone (CVD) vs. no intensification and nonresponders (stable or progressive disease) received CVD. Younger, fitter patients received high-dose melphalan (HDMEL) and autologous stem-cell transplantation, patients were randomized to receive lenalidomide, lenalidomide plus vorinostat, or observation. Maintenance treatment continued until progressive disease in the absence of toxicity (Supplementary Fig. 1). Median time to progression was 20.7 months (range 3.7–71.9 months) and median follow-up 47.0 months. Baseline characteristics are summarized in Supplementary Table 1. The frequency of chromosomal aberrations detectable in the 178 patients at presentation were representative of the overall trial cohort (Supplementary Table 2) [4]. For all patients CD138-positive tumor cells were immunomagnetically selected at presentation and relapse and quality controlled for tumor cell purity (>95%), DNA and RNA were extracted using QIAGEN (Hilden, Germany) Allprep kits. Additional molecular quality control including longitudinal consistency for IgD deletion status was performed for all cases. Matched identity of presentation-relapse pairs was confirmed using single nucleotide and/or insertion/deletion polymorphisms assayed by digitalMLPA D006-X2 for all samples. All patients provided written informed consent. The study was approved by the UK National Research Ethics Service, research ethics committees at participating centers and the UK Medicines and Healthcare Products Regulatory Agency. Translocation and copy number profiling Multiplexed qRT-PCR was used to determine t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20) status in tumors, based on the translocation cyclin D (TC) classification system as previously described [5, 18]. Targeted genome wide CNA status at presentation and relapse in each patient was assessed with a newly developed research version of D006-X2 Multiple Myeloma digitalMLPA probemix, as previously described (Supplementary Methods) [19, 20]. Details of each probe and their respective genomic positions are provided in Supplementary Table 3. CNAs involving sex chromosomes were not considered. CNAs were called if ≥50% of probes mapping to an individual gene or genomic region deviated from normal diploid pattern. Statistical analyses Analyses were performed in R version 3.5.2 using “dplyr”, “tidyr”, “stats”, “survival” and “survminer”, “ComplexHeatmap” and “ggpubr” packages. The association between categorical variables was examined using Fishers exact test and between continuous variables using the Wilcoxon signed-rank test. Progression-free survival (PFS) was defined as time from induction randomization to progression, according to International Myeloma Working Group criteria, or death of any cause. Overall survival (OS) was time from induction randomization to death of any cause. Cox proportional hazards (PH) regression was used to estimate univariate and multivariable hazard ratios (HRs) and 95% confidence intervals (CI). To examine the predictive value of evolution in CNA status for subsequent therapy, high-risk CNA were considered as time dependent covariates within the multivariate model. The PH assumption was tested to investigate whether time dependent covariate effects persisted irrespective of time of acquisition (Supplementary Methods). Multivariate covariates included t(4;14), t(14;16), del(1p), gain(1q), del(17p) and treatment pathway (transplant eligible vs. not). This is relevant because, although the median follow-up of this cohort is long, the inherent requirement of a relapse biopsy excludes the longest responders from our analyses as they are still on active trial medication or observation with no evidence of disease progression. Differences between Kaplan–Meier survival curves was assessed using the log-rank test. A two-sided P value of ≤0.05 was considered statistically significant. Results Acquisition of new CNAs is a feature of relapse Relapse was associated with the acquisition of new CNAs in 87.1% of tumors, most (73.2%) being large-scale chromosome changes. Across all patients, relapse was associated with a higher number of CNAs: median 11.5 (range 0–34) vs. median 12 (range 0–29) (P = 0.0058). As previously well-documented [16, 21], IGH translocations were clonal at presentation and their status did not change at relapse. The most frequent chromosomal changes associated with relapse were gain or amplification of 1q (19%), del(13q) (10%), gain or amplification of 11q (9%) and del(17p)/TP53 in (8%) (Fig. 1; Supplementary Table 2). Although not common, some clonal CNAs detectable at presentation were not detectable at relapse, in particular gain of odd numbered chromosomes in HRD tumors (Supplementary Fig. 2).Fig. 1 Recurrent chromosomal and sub-chromosomal CNA changes at relapse. A Frequency of CNAs emerging at relapse affecting chromosome arms, including new gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green) plotted as a bar graph. B Bar graph showing frequency of 1q, 13q, and 17p CNAs, including gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green), at presentation and relapse. C Heat map of evolving chromosome 1 CNAs at relapse, 63 tumors with change in this region at relapse. On the left (Y-axis) dendrogram representing unsupervised clustering analysis of emerging CNAs in areas interrogated by digitalMLPA probes, which are annotated with gene names and chromosomal location below (X-axis). Change per probe and tumor color-coded as per scale representing normalized digitalMLPA copy number ratios with 1.0 equivalent to normal/diploid. Evolution of sub-chromosomal aberrations In contrast to 1q gain, which generally involved the whole chromosomal arm, clonal 1p deletions tended to be sub-chromosomal (Fig. 1): 1p32.3 deletion (9/178; 5.1%) implicating CDKN2C or 1p12 implicating FAM46C (4/178; 2.2%). In nine of 22 tumors with 1p12 (FAM46C) deletion at diagnosis, the deletion was not clonally detectable at relapse; in contrast all but one of the 8 presentation 1p32.3 (CDKN2C) deletions were detectable at relapse. Focal gain at relapse also affected 8q24.21, involving the MYC locus, in 10/178 (5.6%) tumors. In three of 15 tumors with MYC gain at presentation, reversion to diploid status was a feature of relapse. Sub-chromosomal CNAs involving IMiD response genes—CRBN (3p26.2), IKZF1 (7p12.2), IKZF3 (17q12), and IRF4 (6p25.3)—were infrequent (Supplementary Fig. 3). Most were detectable in tumors relapsing off therapy (no maintenance); only 2 out of 10 were a feature of tumors from patients in receipt of lenalidomide maintenance (1 deletion of CRBN; 1 gain IRF4). Evolution of driver copy number aberrations We next examined for clonal emergence at relapse of sub-clonal changes at diagnosis, focusing on the most frequent drivers—gain(1q) and del(17p). We and others showed before that calling of CNAs using conservative high confidence MLPA cutoff values detects clonal infiltration equivalent to about >20% by FISH, but that calling of minor sub clones is also feasible [4]. Thirty percent of patients’ tumors with clonally detectable 1q gain at relapse had a detectable, potential minor sub-clonal gain(1q) at diagnosis and 50% of del(17p) relapse tumors had potential sub-clonal del(17p) at diagnosis (Supplementary Fig. 4). Progressive clonal expansion of 1q positive tumors was a feature of 17.5% gain(1q) cases, whereby gain at diagnosis evolved into tetraploidy of 1q (amp(1q)) at relapse. Two of 15 tumors with gain of MYC at diagnosis progressed to amplification at relapse. This was also a feature with gain of 15q (4.4%) and 19p (2.3%), albeit at low frequency. We and others have demonstrated that patients with double or triple hit tumors (i.e., 2+ high-risk aberrations t(4;14), t(14;16), t(14;20), gain(1q), or del(17p)) have an especially poor prognosis [4]. It was noteworthy that some tumors with 0 or 1 lesions progressed to carrying double, triple and quadruple hits at relapse (Fig. 2). Amplification 1q has recently been proposed as an additional independent marker of high risk by some researchers [22]. In our study around two thirds of amp(1q) tumors were “double hit”, i.e., also carried t(4;14), t(14;16), t(14;20), or del(17p). Of all 178 relapsed tumors, nearly 10% carried both amp(1q) and “double hit” genetic features (Fig. 2).Fig. 2 Positive selection of co-occurrence of high-risk lesions. A Frequency bar chart of tumors characterized by number of high-risk markers, ranging from no (0) high-risk marker to co-occurrence of 4 markers. B Upset plots of Presentation (left) and Relapse (right) tumors, each showing frequency of individual high-risk lesions (left), type of combination of lesions (center lines with dots indicating presence of individual lesion) and frequency of specific combination of markers (top). C Bar chart showing the overall frequency of amp(1q) between presentation and relapse (overall bar height) and proportion of amp(1q) tumors showing 1q as the only high-risk aberration (single hit), or in combination with one or more other high-risk markers (double hit to quadruple hit). Impact of subtype on copy number profile Given the biological heterogeneity of MM we examined the relationship between CNAs and disease progression by subtype: those with IG translocations (t(4;14), t(11;14), t(14;16)/t(14;20)), and those with HRD, sub-grouped into those with and without gain of 11, in analogy to Translocation and Cyclin D (TC) classification (Supplementary Table 2) [4, 5]. Emerging CNA patterns at relapse were classified as branching (45.5% of all tumors), linear (22.5%), linear loss (19.1%), and stable (12.9%) (Fig. 3). In HRD the majority of tumors showed evidence of branching evolution (57.3%) (Fig. 3). In contrast, linear evolution dominated (36.8%) t(4;14) MM. t(11;14) tumors primarily showed either no CNA change at relapse (stable; 33.3%), or linear evolution (28.6%) (Fig. 3). Importantly, there was no relationship between acquisition of CNAs and either HDMEL or lenalidomide maintenance therapy (Fig. 4).Fig. 3 Relationship between CNAs at presentation and relapse and MM subtype. A Co-occurrence in evolution of novel CNAs at relapse in context of pathogenetic lesions (legend left side; dark bar = present, gray = absent; legend bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position) displayed in a heat map with unsupervised clustering for evolving CNAs. B Frequency of evolutionary patterns across all tumors. C Frequency of evolutionary patterns per major molecular MM subgroups. Fig. 4 Evolutionary patterns in context of trial treatment. A Comparison of frequencies of evolutionary patterns between transplant eligible (TE; younger, fitter patients) and transplant non eligible (TNE). B Comparison of frequencies of evolutionary patterns for patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR) (C) Heatmaps of CNA changes at relapse for tumors from patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR). For each group separately unsupervised clustering on CNA changes was performed and a dendrogram is shown on the left of each heat map. Legend on left side provides context on molecular background lesions (dark bar = present, gray = absent). Legend at bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position. Both del(13) (94.7%) and gain/amp (1q) (68.4%) were seen at high frequency in t(4;14) MM at presentation, and the CNAs were seen at even higher frequencies in relapse tumors at 100% and 79.0%, respectively (Supplementary Fig. 5). Moreover, at relapse del(17p) was a feature of 31.6% of t(4;14) tumors (Supplementary Fig. 5). In contrast, acquisition of 1q, 2p, 8q, 9p, 9q, or 6q CNAs, the changes occurring in t(11;14), were not common; each of these aberration was acquired in <5% of t(11;14) relapsed tumors (Fig. 3). Due to their low frequency, as expected, t(14;16) (two patients) and t(14;20) (one patient) tumors are not discussed; sequential CNA analysis providing limited information regarding subgroup evolutionary trajectory. Baseline and relapse CNAs for t(14;16) and t(14;20) shown in Supplementary Fig. 6. Finally, we examined the relationship between CNA change and MM subtypes defined by CCND expression; CCND1 (D1), CCND2 (D2), or both (D1 + D2) (Supplementary Fig. 7). Acquisition of del(17p) was associated primarily with D2 subtype (Supplementary Fig. 8). Specifically, acquired del(17p) at relapse was a feature of 14.6% of D2, 12.0% of D1 + 2, and 5.1% of D1 tumors. Overall, acquisition of new lesions was less frequent in HRD with gain(11), characterized by D1 expression, vs. other HRD tumors (Supplementary Fig. 9). Associations with patient outcome Gain(1q) (HR = 2.23; P < 0.001), del(1p)/CDKN2C (HR = 1.81; P = 0.046), gain(8q)/MYC (HR = 1.87; P = 0.033), and del(17p) (HR = 2.95; P < 0.001) considered as time dependent variables, i.e., including their acquisition at relapse, were all independently associated with shorter OS (Table 1; Supplementary Fig. 10; Supplementary Table 4).Table 1 Multivariate Cox regression analysis of risk factors for OS, where CNAs represent time dependent covariates. HR 95% CI P value t(4;14) 1.25 (0.62–2.54) 0.53 t(14;16) 1.75 (0.66–4.60) 0.26 Gain(1q) 2.23 (1.39–3.57) 0.0008 Del(1p)/CDKN2C 1.81 (1.01–2.26) 0.046 Gain(8q)/MYC 1.87 (1.05–3.31) 0.033 Del(17p) 2.95 (1.67–5.20) 0.0001 TNE 2.30 (1.41–3.75) 0.0008 HR hazard ratio, 95% CI 95% confidence interval. CNAs were stratified by time point of acquisition, i.e., “Gain-Gain” for those with stable gain and “Diploid-Gain” for those with evolution of gain(1q) at relapse. Gain(1q) from presentation and evolution of new gain(1q) at relapse were both associated with significantly shorter OS compared to normal 1q copy number (HR 2.11; P = 0.0040 and HR 2.00; P = 0.021, respectively). Median OS was 44.3 vs. 47.9 vs. 67.1 months for gain(1q) at diagnosis, new gain(1q) at relapse and normal 1q copy number at both time points, respectively (log-rank P = 0.007) (Fig. 5).Fig. 5 Relationship between emerging CNAs, evolutionary trajectories, and patient outcome. A Kaplan–Meier plot for overall survival in context of presence of CNAs for 1q. Equivalent plots for aberrations of (B) deletion of 1p21 (CDKN2C) (C) gain of 8q21 (MYC) (D) deletion of 17p (TP53) (E) evolutionary pattern. As per individual color-coded label for A–D, curves represent patients with tumors remaining diploid at both time points, changing from diploid to abnormal or showing abnormality at both time points. Acquired del(17p), del(1p/CDKN2C) or gain(8q/MYC) at relapse were not clearly associated with a significantly worse OS in subgroup analyses, although our power to demonstrate a relationship was naturally limited by low frequency of these CNAs. Median OS was 31.3 vs. 60.5 vs. 65.4 months for del(17p) at diagnosis, emergence at relapse and absence at both, respectively (log-rank P < 0.001) (Fig. 5). Median OS was 38.3 vs. 44.6 vs. 63.4 months for del(1p/CDKN2C) at diagnosis, emergence at relapse or absence, respectively (log-rank P = 0.03) (Fig. 5); and for gain(8q/MYC), 38.3 vs. 36.2 vs. 63.4 months, respectively (log-rank P = 0.07) (Fig. 5). Of interest, type of evolutionary pattern was associated with OS; branching evolution was significantly associated with the shortest and linear loss with the longest OS (HR 2.61, P = 0.0048), with median OS being 44.6 vs. 59.6 vs. 62.0 vs. 68.1 months for branching, linear, no change and linear loss respectively (log-rank P = 0.02) (Fig. 5). Discussion Our analysis demonstrates that progression of MM is characterized by emergence of clones with additional large-scale chromosomal changes, commonly involving 1q. Gain or amp(1q) frequently co-evolves with other CNAs, either implicating 1q directly in their genesis as per “jumping 1q” hypothesis, or highlighting 1q as a region providing clonal advantage for genetically instable tumors [23]. While a number of genes on 1q have been proposed as drivers, our study does not provide data to make a specific inference [8, 24–27]. Our findings also suggest progression of MM is associated with positive selection of sub-chromosomal loss of 1p, implicating CDKN2C, and thereby indirectly CDK4/6 in conferring clonal survival benefit at progression. We also identified recurrent sub-chromosomal gain at relapse of an area to which MYC maps (chr8q24.21), in line with its driver role in B-cell malignancies [28, 29]. By considering MM molecular subtype, we highlight differences in evolution trajectories, particularly between HRD and IG translocated MM, but also between t(4;14) and t(11;14) and/or between CCND2 and CCND1 driven tumors [5]. Of note, there is a marked enrichment of acquisition of del(17p) at relapse in CCND2 driven tumors which has, to our knowledge, not been described before. These differences are features of subtypes irrespective of therapy. Our findings are in keeping with published observations for evolution of pre-therapeutic mutational patterns but extend these in context of therapy and relapse [30–32]. We also describe, to our knowledge for the first time, an association between CNA evolution pattern and subsequent outcome. Whether individual CNA evolution pattern has independent clinical relevance and could be included in management considerations at relapse requires further investigation. We identified only a low frequency of CNAs to which IMiD response genes map. In conjuncture with published somatic SNV data, results suggest mutation of these genes per se is not the major determinant of acquired resistance to lenalidomide, or other members of this class of agent in MM [12, 14–16, 33–35]. We demonstrate, to our knowledge for the first time, in a randomized controlled trial that acquisition of gain(1q) at relapse is independently and strongly associated with inferior OS [36]. Although findings are also indicative for del(17p), del(1p/CDKN2C) and gain(8q/MYC), our power to robustly assert clinical relevance of acquired lesions at relapse is inevitably limited by the lower frequency of these CNAs [37]. Clinical evaluation of these markers at relapse is technically feasible in most developed healthcare systems, but currently not widely recommended [38–40]. It is unknown whether sub-clones residing outside of the standard iliac crest bone marrow sampling area at diagnosis are the main source of clonal evolution detected at relapse or whether these predominantly emerge through ongoing genomic instability [12]. Multi-region bone sampling in MM is associated with significant risk and morbidity, making its implementation as part of standard care very challenging. Functional bone marrow soft tissue imaging techniques such as diffusion-weighted whole body MRI and/or molecular techniques including circulating tumor DNA profiling are promising methods in development which may contribute to diagnostic assessment of spatial MM heterogeneity in the future. However, sensitivity, precision and clinical relevance of minor sub-clone detection from a single time point for these methods remains to be established, in particular if results differ from those of parallel bone marrow sampling, before informing clinical management [41–44]. All patients received uniform trial treatment, in particular providing insight into thalidomide and lenalidomide associated CNA changes. However, patients also received low-doses of the oral alkylator cyclophosphamide during induction, which may have specific impact on CNA changes, potentially limiting generalizability of our findings. In addition, molecular information generated with a targeted tool like digitalMLPA is inherently focused and does not discriminate complex processes potentially underlying identified CNAs, such as chromotripsis or chromoplexy, which are detectable by discovery tools such as whole genome sequencing, or single nucleotide variants captured by myeloma specific CNA/sequencing panels [29, 45–47]. Our data also cannot reflect accompanying changes of the tumor microenvironment, which have been implicated in myeloma progression [48]. However, digitalMLPA is in development for clinical diagnostic application, offers sensitive CNA information specific to myeloma from low tumor DNA quantities at high throughput. It requires limited computational infrastructure and uses standardized analysis algorithms, thus overcoming the significant limitations of conventional FISH analysis [20]. As our study demonstrates, digitalMLPA is suitable for longitudinal intra-individual tracking and provides a standardized and accessible method for cross-study validation and putative implementation in molecularly stratified prospective clinical trials. Genetic re-profiling at relapse in MM is currently not widely recommended and, as a consequence, often not reimbursed [10, 39, 49]. Whilst treatment options for relapsed disease were until recently very limited, a range of therapeutic regimens with varying intensity are now approved and available, requiring better tools for clinical decision making at relapse [50–53]. Adapting first-line therapy and its intensity to individual tumor risk markers in MM is now a key focus of research, with multiple genetically stratified prospective clinical trials currently ongoing [10, 54, 55]. The debate about optimal tailoring of second line treatment is likely to intensify with increasing therapeutic options. Our study demonstrates not only the frequency of emerging high-risk CNAs at MM relapse, but also the unmet clinical need of patients with chromosomally evolving MM. These patients should ideally be recognized early during relapse and prospective clinical trials investigating longitudinal management strategies adapted to dynamic risk profiling, designed [56]. Our findings strongly support repeated tumor molecular analysis in MM in context of modern treatment, even in circumstances where only selected markers such as 1q can be tested, as a means of tailoring patient treatment beyond first-line therapy. Supplementary information Supplementary Methods Supplementary Tables Supplementary Figures Supplementary information The online version of this article (10.1038/s41375-020-01096-y) contains supplementary material, which is available to authorized users. Acknowledgements This work was supported by research grants from Celgene, Myeloma UK and the National Institute of Health Biomedical Research Center at the Royal Marsden Hospital and Institute of Cancer Research, London. MFK was supported by a Jacquelin Forbes-Nixon Fellowship. Primary financial support for NCRI Myeloma XI was provided by Cancer Research UK (C1298/A10410). Unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, Ortho Biotech, Amgen, and Merck Sharp & Dohme supported trial coordination. We are grateful for the support of the Clinical Trials Research Unit (CTRU) at Leeds, to the NCRI Haemato-oncology subgroup, investigators and patients. The Myeloma XI trial was conducted with support of the NCRI Hematological Oncology Clinical Studies Group. Author contributions Conception and design: JC, RSH, and MFK. Acquisition of data: all authors. Analysis of data: JC, MFK. Paper writing: JC, RSH, and MFK. Compliance with ethical standards Conflict of interest MWJ: Janssen—consultancy, honoraria, travel support, research funding; Takeda—consultancy, honoraria, travel support; Amgen—consultancy, honoraria, travel support; Celgene Corporation—consultancy, honoraria, research funding; Novartis—consultancy, honoraria. MTD: Abingdon Health—equity ownership, membership on an entity’s board of directors or advisory committees. RGO: Takeda—honoraria, travel support; Janssen—consultancy, travel support; Celgene Corporation—consultancy, honoraria, research funding. JL: Janssen—consultancy; Novartis—travel support; Takeda—honoraria, travel support; Bristol-Myers Squibb—consultancy, travel support; Celgene Corporation—consultancy, honoraria, travel support. KK: Celgene Corporation—travel support, research funding; Janssen—travel support, research funding. WMG: Celgene Corporation—consultancy, research funding; Amgen, Merck Sharp and Dohme—research funding; Janssen—honoraria. FED: Amgen—consultancy, honoraria; AbbVie—consultancy, honoraria; Takeda—consultancy, honoraria; Janssen—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria. GJM: Janssen—research funding; Bristol-Myers Squibb—consultancy, honoraria; Takeda—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria; Amgen—consultancy, honoraria; GSK—consultancy, honoraria; Karyopharm—consultancy, honoraria. GC: Takeda—consultancy, honoraria, research funding, speakers bureau; Glycomimetics—consultancy, honoraria; Sanofi—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, research funding, speakers bureau; Janssen—consultancy, honoraria, research funding, speakers bureau; Bristol-Myers Squibb—consultancy, honoraria; Amgen—consultancy, honoraria, research funding, speakers bureau. LA: MRC-Holland—employment. SS: MRC-Holland—employment. DAC: Celgene Corporation, Amgen, Merck Sharp and Dohme—research funding. GHJ: Roche—consultancy, honoraria, speakers bureau; Amgen—consultancy, honoraria, speakers bureau; Janssen—consultancy, honoraria, speakers bureau; Merck Sharp and Dohme—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, travel support, research funding, speakers bureau; Takeda—consultancy, honoraria, travel support, research funding, speakers bureau. MFK: AbbVie—consultancy; Bristol-Myers Squibb—consultancy, travel support; Chugai—consultancy; GSK—consultancy; Janssen—consultancy, honoraria, research funding; Amgen—consultancy, honoraria; Takeda—consultancy, travel support; Celgene Corporation—consultancy, honoraria, and research funding. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	CARFILZOMIB, CYCLOPHOSPHAMIDE, DEXAMETHASONE	DrugsGivenReaction	CC BY	33262523	20,436,778	2021-07
What was the outcome of reaction 'Death'?	Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial. Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse. Introduction Multiple myeloma (MM) is caused by the malignant clonal expansion of plasma cells in the bone marrow [1]. Approximately 40% of MM tumors harbor chromosome t(4;14), t(11;14), or t(14;16)/t(14;20) translocations, which result in overexpression of oncogenes (including WHSC1/MMSET/NSD2, FGFR3, CCND1, MAF, and MAFB) through juxtaposition to the immunoglobulin heavy-chain locus [2, 3]. Other MM tumors exhibit hyperdiploidy (HRD), which is considered an alternative initiating event. Increased expression of CCND1 in t(11;14) and HRD and increased CCND2 expression in t(4;14), t(14;16)/t(14;20), and HRD are unifying downstream consequences of initiating lesions [4–10]. Recent next-generation sequencing projects have provided insight into the sub-clonal complexity of tumor progression in MM [11–14]. However, few recurrent single nucleotide changes have been reported to be associated with disease relapse, notably sub-clonal mutations of cereblon in immunomodulatory drug (IMiD) treated patients. Knowledge about their prognostic impact remains limited [15]. In contrast, several large-scale chromosomal abnormalities, including gain(1q), del(1p), and del(17p) have been shown to be acquired during tumor progression, but their association with tumor subtype, treatment and outcome is not well understood [11, 16]. Recent studies of the relationship between copy number aberrations (CNAs) and progression of MM have largely been based on short-read sequencing or FISH. Importantly, few studies have been performed on patients from a randomized clinical trial and the impact of therapy on acquisition of CNAs remains unclear [15, 16]. To gain insight into the relationship between CNAs and progression of MM we performed virtual karyotyping of all chromosomes and targeted hotspot profiling using digital multiplexed ligation-dependent probe amplification (digitalMLPA) in matched diagnosis–relapse tumor pairs in 178 UK NCRI Myeloma XI trial patients [17]. We show that acquisition of CNAs is strongly correlated with MM subgroups. Additionally, a number of acquired changes have independent predictive value for defining patient outcome. Material and methods Patients We studied 178 newly diagnosed MM patients enrolled in UK NCRI Myeloma XI (ISRCTN49407852) for which high quality bone marrow tumor material at both presentation and relapse was available. First outcomes of the trial have been published recently [17]. Briefly, patients were initially randomized to triplet induction with thalidomide (CTD), lenalidomide (CRD), or carfilzomib and lenalidomide (KCRD; transplant-eligible patients only) in combination with cyclophosphamide and dexamethasone. Insufficient responders (partial or minimal response) were randomized to cyclophosphamide, bortezomib and dexamethasone (CVD) vs. no intensification and nonresponders (stable or progressive disease) received CVD. Younger, fitter patients received high-dose melphalan (HDMEL) and autologous stem-cell transplantation, patients were randomized to receive lenalidomide, lenalidomide plus vorinostat, or observation. Maintenance treatment continued until progressive disease in the absence of toxicity (Supplementary Fig. 1). Median time to progression was 20.7 months (range 3.7–71.9 months) and median follow-up 47.0 months. Baseline characteristics are summarized in Supplementary Table 1. The frequency of chromosomal aberrations detectable in the 178 patients at presentation were representative of the overall trial cohort (Supplementary Table 2) [4]. For all patients CD138-positive tumor cells were immunomagnetically selected at presentation and relapse and quality controlled for tumor cell purity (>95%), DNA and RNA were extracted using QIAGEN (Hilden, Germany) Allprep kits. Additional molecular quality control including longitudinal consistency for IgD deletion status was performed for all cases. Matched identity of presentation-relapse pairs was confirmed using single nucleotide and/or insertion/deletion polymorphisms assayed by digitalMLPA D006-X2 for all samples. All patients provided written informed consent. The study was approved by the UK National Research Ethics Service, research ethics committees at participating centers and the UK Medicines and Healthcare Products Regulatory Agency. Translocation and copy number profiling Multiplexed qRT-PCR was used to determine t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20) status in tumors, based on the translocation cyclin D (TC) classification system as previously described [5, 18]. Targeted genome wide CNA status at presentation and relapse in each patient was assessed with a newly developed research version of D006-X2 Multiple Myeloma digitalMLPA probemix, as previously described (Supplementary Methods) [19, 20]. Details of each probe and their respective genomic positions are provided in Supplementary Table 3. CNAs involving sex chromosomes were not considered. CNAs were called if ≥50% of probes mapping to an individual gene or genomic region deviated from normal diploid pattern. Statistical analyses Analyses were performed in R version 3.5.2 using “dplyr”, “tidyr”, “stats”, “survival” and “survminer”, “ComplexHeatmap” and “ggpubr” packages. The association between categorical variables was examined using Fishers exact test and between continuous variables using the Wilcoxon signed-rank test. Progression-free survival (PFS) was defined as time from induction randomization to progression, according to International Myeloma Working Group criteria, or death of any cause. Overall survival (OS) was time from induction randomization to death of any cause. Cox proportional hazards (PH) regression was used to estimate univariate and multivariable hazard ratios (HRs) and 95% confidence intervals (CI). To examine the predictive value of evolution in CNA status for subsequent therapy, high-risk CNA were considered as time dependent covariates within the multivariate model. The PH assumption was tested to investigate whether time dependent covariate effects persisted irrespective of time of acquisition (Supplementary Methods). Multivariate covariates included t(4;14), t(14;16), del(1p), gain(1q), del(17p) and treatment pathway (transplant eligible vs. not). This is relevant because, although the median follow-up of this cohort is long, the inherent requirement of a relapse biopsy excludes the longest responders from our analyses as they are still on active trial medication or observation with no evidence of disease progression. Differences between Kaplan–Meier survival curves was assessed using the log-rank test. A two-sided P value of ≤0.05 was considered statistically significant. Results Acquisition of new CNAs is a feature of relapse Relapse was associated with the acquisition of new CNAs in 87.1% of tumors, most (73.2%) being large-scale chromosome changes. Across all patients, relapse was associated with a higher number of CNAs: median 11.5 (range 0–34) vs. median 12 (range 0–29) (P = 0.0058). As previously well-documented [16, 21], IGH translocations were clonal at presentation and their status did not change at relapse. The most frequent chromosomal changes associated with relapse were gain or amplification of 1q (19%), del(13q) (10%), gain or amplification of 11q (9%) and del(17p)/TP53 in (8%) (Fig. 1; Supplementary Table 2). Although not common, some clonal CNAs detectable at presentation were not detectable at relapse, in particular gain of odd numbered chromosomes in HRD tumors (Supplementary Fig. 2).Fig. 1 Recurrent chromosomal and sub-chromosomal CNA changes at relapse. A Frequency of CNAs emerging at relapse affecting chromosome arms, including new gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green) plotted as a bar graph. B Bar graph showing frequency of 1q, 13q, and 17p CNAs, including gain (red), amplification (yellow), heterozygous deletion (blue), or homozygous deletion (green), at presentation and relapse. C Heat map of evolving chromosome 1 CNAs at relapse, 63 tumors with change in this region at relapse. On the left (Y-axis) dendrogram representing unsupervised clustering analysis of emerging CNAs in areas interrogated by digitalMLPA probes, which are annotated with gene names and chromosomal location below (X-axis). Change per probe and tumor color-coded as per scale representing normalized digitalMLPA copy number ratios with 1.0 equivalent to normal/diploid. Evolution of sub-chromosomal aberrations In contrast to 1q gain, which generally involved the whole chromosomal arm, clonal 1p deletions tended to be sub-chromosomal (Fig. 1): 1p32.3 deletion (9/178; 5.1%) implicating CDKN2C or 1p12 implicating FAM46C (4/178; 2.2%). In nine of 22 tumors with 1p12 (FAM46C) deletion at diagnosis, the deletion was not clonally detectable at relapse; in contrast all but one of the 8 presentation 1p32.3 (CDKN2C) deletions were detectable at relapse. Focal gain at relapse also affected 8q24.21, involving the MYC locus, in 10/178 (5.6%) tumors. In three of 15 tumors with MYC gain at presentation, reversion to diploid status was a feature of relapse. Sub-chromosomal CNAs involving IMiD response genes—CRBN (3p26.2), IKZF1 (7p12.2), IKZF3 (17q12), and IRF4 (6p25.3)—were infrequent (Supplementary Fig. 3). Most were detectable in tumors relapsing off therapy (no maintenance); only 2 out of 10 were a feature of tumors from patients in receipt of lenalidomide maintenance (1 deletion of CRBN; 1 gain IRF4). Evolution of driver copy number aberrations We next examined for clonal emergence at relapse of sub-clonal changes at diagnosis, focusing on the most frequent drivers—gain(1q) and del(17p). We and others showed before that calling of CNAs using conservative high confidence MLPA cutoff values detects clonal infiltration equivalent to about >20% by FISH, but that calling of minor sub clones is also feasible [4]. Thirty percent of patients’ tumors with clonally detectable 1q gain at relapse had a detectable, potential minor sub-clonal gain(1q) at diagnosis and 50% of del(17p) relapse tumors had potential sub-clonal del(17p) at diagnosis (Supplementary Fig. 4). Progressive clonal expansion of 1q positive tumors was a feature of 17.5% gain(1q) cases, whereby gain at diagnosis evolved into tetraploidy of 1q (amp(1q)) at relapse. Two of 15 tumors with gain of MYC at diagnosis progressed to amplification at relapse. This was also a feature with gain of 15q (4.4%) and 19p (2.3%), albeit at low frequency. We and others have demonstrated that patients with double or triple hit tumors (i.e., 2+ high-risk aberrations t(4;14), t(14;16), t(14;20), gain(1q), or del(17p)) have an especially poor prognosis [4]. It was noteworthy that some tumors with 0 or 1 lesions progressed to carrying double, triple and quadruple hits at relapse (Fig. 2). Amplification 1q has recently been proposed as an additional independent marker of high risk by some researchers [22]. In our study around two thirds of amp(1q) tumors were “double hit”, i.e., also carried t(4;14), t(14;16), t(14;20), or del(17p). Of all 178 relapsed tumors, nearly 10% carried both amp(1q) and “double hit” genetic features (Fig. 2).Fig. 2 Positive selection of co-occurrence of high-risk lesions. A Frequency bar chart of tumors characterized by number of high-risk markers, ranging from no (0) high-risk marker to co-occurrence of 4 markers. B Upset plots of Presentation (left) and Relapse (right) tumors, each showing frequency of individual high-risk lesions (left), type of combination of lesions (center lines with dots indicating presence of individual lesion) and frequency of specific combination of markers (top). C Bar chart showing the overall frequency of amp(1q) between presentation and relapse (overall bar height) and proportion of amp(1q) tumors showing 1q as the only high-risk aberration (single hit), or in combination with one or more other high-risk markers (double hit to quadruple hit). Impact of subtype on copy number profile Given the biological heterogeneity of MM we examined the relationship between CNAs and disease progression by subtype: those with IG translocations (t(4;14), t(11;14), t(14;16)/t(14;20)), and those with HRD, sub-grouped into those with and without gain of 11, in analogy to Translocation and Cyclin D (TC) classification (Supplementary Table 2) [4, 5]. Emerging CNA patterns at relapse were classified as branching (45.5% of all tumors), linear (22.5%), linear loss (19.1%), and stable (12.9%) (Fig. 3). In HRD the majority of tumors showed evidence of branching evolution (57.3%) (Fig. 3). In contrast, linear evolution dominated (36.8%) t(4;14) MM. t(11;14) tumors primarily showed either no CNA change at relapse (stable; 33.3%), or linear evolution (28.6%) (Fig. 3). Importantly, there was no relationship between acquisition of CNAs and either HDMEL or lenalidomide maintenance therapy (Fig. 4).Fig. 3 Relationship between CNAs at presentation and relapse and MM subtype. A Co-occurrence in evolution of novel CNAs at relapse in context of pathogenetic lesions (legend left side; dark bar = present, gray = absent; legend bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position) displayed in a heat map with unsupervised clustering for evolving CNAs. B Frequency of evolutionary patterns across all tumors. C Frequency of evolutionary patterns per major molecular MM subgroups. Fig. 4 Evolutionary patterns in context of trial treatment. A Comparison of frequencies of evolutionary patterns between transplant eligible (TE; younger, fitter patients) and transplant non eligible (TNE). B Comparison of frequencies of evolutionary patterns for patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR) (C) Heatmaps of CNA changes at relapse for tumors from patients randomized to lenalidomide (L) maintenance, observation (O) or those not randomized (NR). For each group separately unsupervised clustering on CNA changes was performed and a dendrogram is shown on the left of each heat map. Legend on left side provides context on molecular background lesions (dark bar = present, gray = absent). Legend at bottom: black and white bands representing chromosomal mapping of digitalMLPA probes chr1-22 from left to right in ascending order of genomic position. Both del(13) (94.7%) and gain/amp (1q) (68.4%) were seen at high frequency in t(4;14) MM at presentation, and the CNAs were seen at even higher frequencies in relapse tumors at 100% and 79.0%, respectively (Supplementary Fig. 5). Moreover, at relapse del(17p) was a feature of 31.6% of t(4;14) tumors (Supplementary Fig. 5). In contrast, acquisition of 1q, 2p, 8q, 9p, 9q, or 6q CNAs, the changes occurring in t(11;14), were not common; each of these aberration was acquired in <5% of t(11;14) relapsed tumors (Fig. 3). Due to their low frequency, as expected, t(14;16) (two patients) and t(14;20) (one patient) tumors are not discussed; sequential CNA analysis providing limited information regarding subgroup evolutionary trajectory. Baseline and relapse CNAs for t(14;16) and t(14;20) shown in Supplementary Fig. 6. Finally, we examined the relationship between CNA change and MM subtypes defined by CCND expression; CCND1 (D1), CCND2 (D2), or both (D1 + D2) (Supplementary Fig. 7). Acquisition of del(17p) was associated primarily with D2 subtype (Supplementary Fig. 8). Specifically, acquired del(17p) at relapse was a feature of 14.6% of D2, 12.0% of D1 + 2, and 5.1% of D1 tumors. Overall, acquisition of new lesions was less frequent in HRD with gain(11), characterized by D1 expression, vs. other HRD tumors (Supplementary Fig. 9). Associations with patient outcome Gain(1q) (HR = 2.23; P < 0.001), del(1p)/CDKN2C (HR = 1.81; P = 0.046), gain(8q)/MYC (HR = 1.87; P = 0.033), and del(17p) (HR = 2.95; P < 0.001) considered as time dependent variables, i.e., including their acquisition at relapse, were all independently associated with shorter OS (Table 1; Supplementary Fig. 10; Supplementary Table 4).Table 1 Multivariate Cox regression analysis of risk factors for OS, where CNAs represent time dependent covariates. HR 95% CI P value t(4;14) 1.25 (0.62–2.54) 0.53 t(14;16) 1.75 (0.66–4.60) 0.26 Gain(1q) 2.23 (1.39–3.57) 0.0008 Del(1p)/CDKN2C 1.81 (1.01–2.26) 0.046 Gain(8q)/MYC 1.87 (1.05–3.31) 0.033 Del(17p) 2.95 (1.67–5.20) 0.0001 TNE 2.30 (1.41–3.75) 0.0008 HR hazard ratio, 95% CI 95% confidence interval. CNAs were stratified by time point of acquisition, i.e., “Gain-Gain” for those with stable gain and “Diploid-Gain” for those with evolution of gain(1q) at relapse. Gain(1q) from presentation and evolution of new gain(1q) at relapse were both associated with significantly shorter OS compared to normal 1q copy number (HR 2.11; P = 0.0040 and HR 2.00; P = 0.021, respectively). Median OS was 44.3 vs. 47.9 vs. 67.1 months for gain(1q) at diagnosis, new gain(1q) at relapse and normal 1q copy number at both time points, respectively (log-rank P = 0.007) (Fig. 5).Fig. 5 Relationship between emerging CNAs, evolutionary trajectories, and patient outcome. A Kaplan–Meier plot for overall survival in context of presence of CNAs for 1q. Equivalent plots for aberrations of (B) deletion of 1p21 (CDKN2C) (C) gain of 8q21 (MYC) (D) deletion of 17p (TP53) (E) evolutionary pattern. As per individual color-coded label for A–D, curves represent patients with tumors remaining diploid at both time points, changing from diploid to abnormal or showing abnormality at both time points. Acquired del(17p), del(1p/CDKN2C) or gain(8q/MYC) at relapse were not clearly associated with a significantly worse OS in subgroup analyses, although our power to demonstrate a relationship was naturally limited by low frequency of these CNAs. Median OS was 31.3 vs. 60.5 vs. 65.4 months for del(17p) at diagnosis, emergence at relapse and absence at both, respectively (log-rank P < 0.001) (Fig. 5). Median OS was 38.3 vs. 44.6 vs. 63.4 months for del(1p/CDKN2C) at diagnosis, emergence at relapse or absence, respectively (log-rank P = 0.03) (Fig. 5); and for gain(8q/MYC), 38.3 vs. 36.2 vs. 63.4 months, respectively (log-rank P = 0.07) (Fig. 5). Of interest, type of evolutionary pattern was associated with OS; branching evolution was significantly associated with the shortest and linear loss with the longest OS (HR 2.61, P = 0.0048), with median OS being 44.6 vs. 59.6 vs. 62.0 vs. 68.1 months for branching, linear, no change and linear loss respectively (log-rank P = 0.02) (Fig. 5). Discussion Our analysis demonstrates that progression of MM is characterized by emergence of clones with additional large-scale chromosomal changes, commonly involving 1q. Gain or amp(1q) frequently co-evolves with other CNAs, either implicating 1q directly in their genesis as per “jumping 1q” hypothesis, or highlighting 1q as a region providing clonal advantage for genetically instable tumors [23]. While a number of genes on 1q have been proposed as drivers, our study does not provide data to make a specific inference [8, 24–27]. Our findings also suggest progression of MM is associated with positive selection of sub-chromosomal loss of 1p, implicating CDKN2C, and thereby indirectly CDK4/6 in conferring clonal survival benefit at progression. We also identified recurrent sub-chromosomal gain at relapse of an area to which MYC maps (chr8q24.21), in line with its driver role in B-cell malignancies [28, 29]. By considering MM molecular subtype, we highlight differences in evolution trajectories, particularly between HRD and IG translocated MM, but also between t(4;14) and t(11;14) and/or between CCND2 and CCND1 driven tumors [5]. Of note, there is a marked enrichment of acquisition of del(17p) at relapse in CCND2 driven tumors which has, to our knowledge, not been described before. These differences are features of subtypes irrespective of therapy. Our findings are in keeping with published observations for evolution of pre-therapeutic mutational patterns but extend these in context of therapy and relapse [30–32]. We also describe, to our knowledge for the first time, an association between CNA evolution pattern and subsequent outcome. Whether individual CNA evolution pattern has independent clinical relevance and could be included in management considerations at relapse requires further investigation. We identified only a low frequency of CNAs to which IMiD response genes map. In conjuncture with published somatic SNV data, results suggest mutation of these genes per se is not the major determinant of acquired resistance to lenalidomide, or other members of this class of agent in MM [12, 14–16, 33–35]. We demonstrate, to our knowledge for the first time, in a randomized controlled trial that acquisition of gain(1q) at relapse is independently and strongly associated with inferior OS [36]. Although findings are also indicative for del(17p), del(1p/CDKN2C) and gain(8q/MYC), our power to robustly assert clinical relevance of acquired lesions at relapse is inevitably limited by the lower frequency of these CNAs [37]. Clinical evaluation of these markers at relapse is technically feasible in most developed healthcare systems, but currently not widely recommended [38–40]. It is unknown whether sub-clones residing outside of the standard iliac crest bone marrow sampling area at diagnosis are the main source of clonal evolution detected at relapse or whether these predominantly emerge through ongoing genomic instability [12]. Multi-region bone sampling in MM is associated with significant risk and morbidity, making its implementation as part of standard care very challenging. Functional bone marrow soft tissue imaging techniques such as diffusion-weighted whole body MRI and/or molecular techniques including circulating tumor DNA profiling are promising methods in development which may contribute to diagnostic assessment of spatial MM heterogeneity in the future. However, sensitivity, precision and clinical relevance of minor sub-clone detection from a single time point for these methods remains to be established, in particular if results differ from those of parallel bone marrow sampling, before informing clinical management [41–44]. All patients received uniform trial treatment, in particular providing insight into thalidomide and lenalidomide associated CNA changes. However, patients also received low-doses of the oral alkylator cyclophosphamide during induction, which may have specific impact on CNA changes, potentially limiting generalizability of our findings. In addition, molecular information generated with a targeted tool like digitalMLPA is inherently focused and does not discriminate complex processes potentially underlying identified CNAs, such as chromotripsis or chromoplexy, which are detectable by discovery tools such as whole genome sequencing, or single nucleotide variants captured by myeloma specific CNA/sequencing panels [29, 45–47]. Our data also cannot reflect accompanying changes of the tumor microenvironment, which have been implicated in myeloma progression [48]. However, digitalMLPA is in development for clinical diagnostic application, offers sensitive CNA information specific to myeloma from low tumor DNA quantities at high throughput. It requires limited computational infrastructure and uses standardized analysis algorithms, thus overcoming the significant limitations of conventional FISH analysis [20]. As our study demonstrates, digitalMLPA is suitable for longitudinal intra-individual tracking and provides a standardized and accessible method for cross-study validation and putative implementation in molecularly stratified prospective clinical trials. Genetic re-profiling at relapse in MM is currently not widely recommended and, as a consequence, often not reimbursed [10, 39, 49]. Whilst treatment options for relapsed disease were until recently very limited, a range of therapeutic regimens with varying intensity are now approved and available, requiring better tools for clinical decision making at relapse [50–53]. Adapting first-line therapy and its intensity to individual tumor risk markers in MM is now a key focus of research, with multiple genetically stratified prospective clinical trials currently ongoing [10, 54, 55]. The debate about optimal tailoring of second line treatment is likely to intensify with increasing therapeutic options. Our study demonstrates not only the frequency of emerging high-risk CNAs at MM relapse, but also the unmet clinical need of patients with chromosomally evolving MM. These patients should ideally be recognized early during relapse and prospective clinical trials investigating longitudinal management strategies adapted to dynamic risk profiling, designed [56]. Our findings strongly support repeated tumor molecular analysis in MM in context of modern treatment, even in circumstances where only selected markers such as 1q can be tested, as a means of tailoring patient treatment beyond first-line therapy. Supplementary information Supplementary Methods Supplementary Tables Supplementary Figures Supplementary information The online version of this article (10.1038/s41375-020-01096-y) contains supplementary material, which is available to authorized users. Acknowledgements This work was supported by research grants from Celgene, Myeloma UK and the National Institute of Health Biomedical Research Center at the Royal Marsden Hospital and Institute of Cancer Research, London. MFK was supported by a Jacquelin Forbes-Nixon Fellowship. Primary financial support for NCRI Myeloma XI was provided by Cancer Research UK (C1298/A10410). Unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, Ortho Biotech, Amgen, and Merck Sharp & Dohme supported trial coordination. We are grateful for the support of the Clinical Trials Research Unit (CTRU) at Leeds, to the NCRI Haemato-oncology subgroup, investigators and patients. The Myeloma XI trial was conducted with support of the NCRI Hematological Oncology Clinical Studies Group. Author contributions Conception and design: JC, RSH, and MFK. Acquisition of data: all authors. Analysis of data: JC, MFK. Paper writing: JC, RSH, and MFK. Compliance with ethical standards Conflict of interest MWJ: Janssen—consultancy, honoraria, travel support, research funding; Takeda—consultancy, honoraria, travel support; Amgen—consultancy, honoraria, travel support; Celgene Corporation—consultancy, honoraria, research funding; Novartis—consultancy, honoraria. MTD: Abingdon Health—equity ownership, membership on an entity’s board of directors or advisory committees. RGO: Takeda—honoraria, travel support; Janssen—consultancy, travel support; Celgene Corporation—consultancy, honoraria, research funding. JL: Janssen—consultancy; Novartis—travel support; Takeda—honoraria, travel support; Bristol-Myers Squibb—consultancy, travel support; Celgene Corporation—consultancy, honoraria, travel support. KK: Celgene Corporation—travel support, research funding; Janssen—travel support, research funding. WMG: Celgene Corporation—consultancy, research funding; Amgen, Merck Sharp and Dohme—research funding; Janssen—honoraria. FED: Amgen—consultancy, honoraria; AbbVie—consultancy, honoraria; Takeda—consultancy, honoraria; Janssen—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria. GJM: Janssen—research funding; Bristol-Myers Squibb—consultancy, honoraria; Takeda—consultancy, honoraria; Celgene Corporation—consultancy, honoraria, research funding; Roche—consultancy, honoraria; Amgen—consultancy, honoraria; GSK—consultancy, honoraria; Karyopharm—consultancy, honoraria. GC: Takeda—consultancy, honoraria, research funding, speakers bureau; Glycomimetics—consultancy, honoraria; Sanofi—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, research funding, speakers bureau; Janssen—consultancy, honoraria, research funding, speakers bureau; Bristol-Myers Squibb—consultancy, honoraria; Amgen—consultancy, honoraria, research funding, speakers bureau. LA: MRC-Holland—employment. SS: MRC-Holland—employment. DAC: Celgene Corporation, Amgen, Merck Sharp and Dohme—research funding. GHJ: Roche—consultancy, honoraria, speakers bureau; Amgen—consultancy, honoraria, speakers bureau; Janssen—consultancy, honoraria, speakers bureau; Merck Sharp and Dohme—consultancy, honoraria, speakers bureau; Celgene Corporation—consultancy, honoraria, travel support, research funding, speakers bureau; Takeda—consultancy, honoraria, travel support, research funding, speakers bureau. MFK: AbbVie—consultancy; Bristol-Myers Squibb—consultancy, travel support; Chugai—consultancy; GSK—consultancy; Janssen—consultancy, honoraria, research funding; Amgen—consultancy, honoraria; Takeda—consultancy, travel support; Celgene Corporation—consultancy, honoraria, and research funding. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Fatal	ReactionOutcome	CC BY	33262523	20,436,778	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'.	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, DEXAMETHASONE, ENOXAPARIN, HEPARIN SODIUM, REMDESIVIR	DrugsGivenReaction	CC BY-NC-ND	33262932	18,730,194	2021-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, DEXAMETHASONE, ENOXAPARIN, FUROSEMIDE, HEPARIN SODIUM, INSULIN NOS, REMDESIVIR	DrugsGivenReaction	CC BY-NC-ND	33262932	18,868,538	2021-01
What is the weight of the patient?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	1.31 kg.	Weight	CC BY-NC-ND	33262932	18,703,859	2021-01
What was the administration route of drug 'AZITHROMYCIN ANHYDROUS'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,831,127	2021-01
What was the administration route of drug 'CEFTRIAXONE'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,831,127	2021-01
What was the administration route of drug 'ENOXAPARIN'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,730,438	2021-01
What was the administration route of drug 'FUROSEMIDE'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,831,127	2021-01
What was the administration route of drug 'HEPARIN SODIUM'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,730,438	2021-01
What was the administration route of drug 'INSULIN NOS'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,831,127	2021-01
What was the administration route of drug 'OXYGEN'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,831,127	2021-01
What was the administration route of drug 'REMDESIVIR'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Transplacental	DrugAdministrationRoute	CC BY-NC-ND	33262932	18,831,127	2021-01
What was the dosage of drug 'FUROSEMIDE'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	MATERNAL DOSE ?UNK	DrugDosageText	CC BY-NC-ND	33262932	18,707,918	2021-01
What was the dosage of drug 'INSULIN NOS'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	MATERNAL DOSE: UNK	DrugDosageText	CC BY-NC-ND	33262932	18,707,918	2021-01
What was the outcome of reaction 'Adrenal insufficiency'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Recovered	ReactionOutcome	CC BY-NC-ND	33262932	18,730,438	2021-01
What was the outcome of reaction 'Exposure during pregnancy'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Recovered	ReactionOutcome	CC BY-NC-ND	33262932	18,730,194	2021-01
What was the outcome of reaction 'Foetal exposure during pregnancy'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Recovered	ReactionOutcome	CC BY-NC-ND	33262932	18,730,438	2021-01
What was the outcome of reaction 'Hyperglycaemia'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Recovered	ReactionOutcome	CC BY-NC-ND	33262932	18,730,194	2021-01
What was the outcome of reaction 'Premature baby'?	Use of dexamethasone, remdesivir, convalescent plasma and prone positioning in the treatment of severe COVID-19 infection in pregnancy: A case report. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. We report the case of a woman at 26 weeks of gestation with acute respiratory distress syndrome secondary to COVID-19 infection treated with dexamethasone, remdesivir, convalescent plasma and mechanical ventilation. Cesarean delivery was performed at 29 weeks due to worsening maternal status. This case offers insight into the assessment and successful use of treatment strategies, including dexamethasone, remdesivir, convalescent plasma, early prone positioning, conservative fluid management, permissive hypoxia and low tidal volume parameters with ventilator support for pregnancies affected by severe COVID-19 infection. 1 Introduction The mainstay of intensive care treatment for acute hypoxic respiratory failure due to severe COVID-19 infection is supportive with supplemental oxygen or invasive mechanical ventilation, judicious fluid management, systemic corticosteroids, and early use of vasoactive medications. Patients are monitored closely for the development of viral myocarditis, thrombotic events, and superimposed bacterial pneumonia. Several experimental drug and other therapies are currently being studied, including remdesivir, lopinavir-ritonavir, tocilizumab, azithromycin, Bacillus Calmette–Guérin vaccine and convalescent plasma [[1], [2], [3]]. Severe infection with COVID-19 virus in pregnancy offers unique management challenges for the obstetrician and critical care specialist. Special consideration must be undertaken regarding oxygenation and respiratory support, fluid management, use of corticosteroids and experimental therapeutics, anticoagulation, and fetal monitoring, often with limited evidence-based recommendations. This case offers insight into the assessment and use of these management strategies, most specifically the use of dexamethasone and critical care strategies with early prone positioning in those requiring ventilator support. 2 Case Presentation A 42-year-old woman, G8P6016, presented to an outside hospital in acute hypoxic respiratory failure at 26 weeks of gestation. She had no underlying medical history. She presented with a week of increasing dyspnea and a productive cough; a PCR test for COVID-19 the day prior was positive. She was febrile with an oxygen saturation (SpO2) of 78% on room air, and respiratory rate of 50–60. Her SpO2 remained in the 80s by pulse oximetry despite 15 L of oxygen by non-rebreather mask and ABG showed a pH 7.42, pCO2 24.3, PaO2 46.7, HCO3 15.7, Base deficit −8.7 and O2 saturation 84.3. Chest x-ray demonstrated diffuse bilateral consolidations and clinical exam revealed coarse, diminished breath sounds. She was intubated and transferred to a tertiary care center. Upon arrival, SpO2 remained 85% on FiO2 of 100% and PEEP of 12 but improved to 93–95% with placement in prone position, paralysis and sedation, and adjustment of ventilator settings to 6 cc/kg with increased PEEP. A low tidal volume strategy was employed for lung protection in the setting of acute respiratory distress syndrome (ARDS) [4]. The patient remained in prone positioning for 16–18 h daily to assist with ventilation [5,6]. She received dexamethasone 20 mg IV for 5 days followed by 10 mg IV for 5 days [7,8], remdesivir 200 mg × 1 then 100 mg every 24 h for 9 days [1], and convalescent plasma [2] on HD2. She received azithromycin and ceftriaxone for empiric treatment of possible superimposed bacterial pneumonia [3]. Bilateral upper and lower extremity Doppler and coagulation studies were completed to assess for hypercoagulability. Therapeutic enoxaparin was initiated after identifying a basilic vein thrombosis near the upper extremity PICC site. She was eventually transitioned to a heparin infusion to allow reversal of anticoagulation in case of urgent delivery. She required an insulin infusion to maintain euglycemia through the day of delivery, suggesting both steroid-induced hyperglycemia and some degree of undiagnosed gestational diabetes. Continuous external fetal monitoring (EFM) was performed from admission to delivery. Fetal status remained reassuring throughout her hospitalization except for a period of prolonged, 8-min fetal heart rate (FHR) deceleration occurring during maternal position change from prone to supine, but recovered with standard intrauterine resuscitation measures. On HD11, ventilator requirements gradually increased after a period of initial stabilization and SpO2 of 95% or higher could not be maintained without risking barotrauma. After interdisciplinary discussion, this goal was adjusted to maintain SpO2 of 90% or higher if fetal wellbeing was reassuring. This adjustment was well tolerated and allowed the pregnancy to be continued for an additional week. The evening of HD16, she was noted to have progressive hypoxia, declining lung compliance and increasing plateau pressures, requiring increasing ventilator support parameters and diuresis with furosemide to maintain SpO2 at 90%. On HD17, Critical Care and Maternal-Fetal Medicine (MFM) discussed the therapeutic option of ECMO support in concert with cardiothoracic surgery but ultimately this was deemed to be higher risk than proceeding with cesarean delivery. Anticoagulation was held and primary cesarean delivery was performed at 29 weeks 1 day via vertical skin incision and low transverse hysterotomy. Cesarean delivery was performed in the ICU with Critical Care, MFM, Neonatology and Anesthesia teams present. A live male infant weighing 1310 g with APGAR scores of 31 and 65 was delivered and admitted to the NICU. Arterial umbilical cord blood gases showed pH of 7.25, pCO2 79, pO2 17 and base excess 3.8. Amniotic fluid and placenta cultured negative for COVID-19. Placental pathology was only notable for few patchy areas consistent with maternal vascular malperfusion. Subsequent testing of the infant on DOL 3 and DOL 14 were negative for COVID-19. Following delivery, the patient quickly tolerated increasing durations of supine positioning, improved lung compliance, reduction in plateau pressures, and ability to wean FiO2 and PEEP settings. Due to continued fevers, she underwent bronchoscopy on HD18 and two sputum cultures showed growth of Enterobacter cloacae, which was treated with cefepime. On HD30, she underwent tracheostomy. She was weaned from the ventilator and transferred to intermediate care on HD40. The tracheostomy was decannulated on HD50 and she was discharged to home on HD52 requiring home oxygen at night and continued nursing care. The infant experienced adrenal insufficiency, likely due to maternal dexamethasone treatment; however, overall, the infant had an uncomplicated NICU course and was discharged home on DOL 57, a postmenstrual age of 37 weeks, in good condition. 3 Discussion This case of severe COVID-19 infection in pregnancy required prone positioning, mechanical ventilation and the use of experimental treatment therapies. Our experience is unique given the rapidly changing course of recommended treatment for individuals with COVID-19. At the time of clinical decision making, no obstetric guidelines were available supporting the use of dexamethasone in pregnancy. With extensive discussion, we elected to administer this for the benefit of decreased morbidity among those receiving invasive respiratory treatment in COVID-19 infection, supported by both RECOVERY trial data [9] and data on use of dexamethasone in ARDS [7,8], as this outweighed the risk for fetal harm with prolonged corticosteroid exposure beyond the typical 4 doses of dexamethasone 6 mg used for fetal lung maturity [10,11]. One notable potential outcome for providers when considering use of dexamethasone is adrenal insufficiency in the neonate. The neonate was initially treated with hydrocortisone from DOL 1 to DOL 5 due to in utero prolonged exposure to dexamethasone; however, cortisol levels remained low at both DOL 18 (63.48 nmol/L) and DOL 56 (33.40 nmol/L), diagnosing adrenal insufficiency. This infant will require stress-dosing of steroids with any future surgery or signs of clinical illness. Beyond low tidal volume strategies for lung protection in ARDS, a conservative fluid management approach has been demonstrated to improve lung function and shorten mechanical ventilation without an increase in non-pulmonary organ failure [15] and this was safely used in the pregnant state. Furosemide was used for fluid management and can be used in pregnancy for diuresis as needed [16]. Another point of discussion is the goal for maintenance of O2 saturations. In pregnancy, it is recommended to maintain SpO2 of 95% or greater [12,13] and 92% or greater in non-pregnant patients, particularly with COVID-19 [14]. In this case, permissive hypoxia to SpO2 of 90% or greater was utilized for maternal lung protection given reassuring fetal status by EFM and allowed this pre-term pregnancy to continue an additional week for fetal benefit. The question of vertical transmission of COVID-19 in pregnancy is still under investigation. COVID-19 cultures were collected from the amniotic fluid and placenta at delivery and returned negative; however, it is worth noting that due to novel testing and laboratory processing procedures, these specimen sources have not yet been validated at our institution. Subsequent negative neonatal testing in this case does, however, strengthen their reliability. 4 Conclusion Dexamethasone may provide significant maternal benefit and decrease mortality in pregnant women with severe COVID-19 infection requiring mechanical ventilation and at the same time promote fetal lung maturity. Neonatal concerns regarding its use in pregnancy include hyperglycemia with resulting neonatal hypoglycemia as well as the potential for the development of adrenal insufficiency. Generally, maternal benefit of this protocol outweighs risks of neonatal harm in the critically ill patient. None of the experimental clinical therapeutics are consider contraindicated and compassionate use of these therapeutics should be considered in pregnant women with severe illness due to COVID-19. Lung protective ventilator strategies for COVID-related ARDS are well tolerated in the pregnant patient. Use of prone positioning in the pregnant patient was achieved safely, with oxygenation benefit and no prolonged distress to the fetus noted over routine 16 to 18 h of prone positioning. When supine, a left lateral tilt was employed to avoid compression of the inferior vena cava and aorta by the gravid uterus. A conservative fluid management approach with ARDS as well as diuresis can safely be used in pregnancy. Fetal heart rate tracing can offer an additional clinical indicator of maternal oxygenation status and should be employed in the critically ill pregnant patient. Permissive hypoxia may be considered to advance fetal maturity and minimize barotrauma, but this approach should be undertaken with caution and only with continuous EFM to ensure fetal tolerance. Appendix A Supplementary data The Care Checklist Image 1 Contributors Jennifer Jacobson drafted the paper and is the lead author. Kathleen Antony contributed to critical revision of the paper. Michael Beninati contributed to critical revision of the paper. William Alward contributed to critical revision of the paper. Kara K. Hoppe contributed to critical revision of the paper. Conflict of Interest The authors declare that they have no conflict of interest regarding the publication of this case report. Funding No funding from an external source supported the publication of this case report. Patient Consent Obtained. Provenance and Peer Review This case report was peer reviewed. Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.crwh.2020.e00273.	Recovered	ReactionOutcome	CC BY-NC-ND	33262932	18,621,424	2021-01
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse event'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Angiopathy'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Benign neoplasm'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breast disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Connective tissue disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ear disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Endocrine disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eye disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatobiliary disease'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune system disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphatic disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malnutrition'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mental disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metabolic disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Musculoskeletal disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neoplasm malignant'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neoplasm'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nervous system disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Reproductive tract disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Social problem'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urinary tract disorder'.	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	ADALIMUMAB, APREMILAST, CYCLOSPORINE, INFLIXIMAB, IXEKIZUMAB, METHOTREXATE, SECUKINUMAB, USTEKINUMAB	DrugsGivenReaction	CC BY-NC	33269405	18,973,641	2021-01-04
What was the outcome of reaction 'Death'?	Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort. The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness. pmcSex differences are recognized in medicine (1), and analysis of inequalities in practice care may be based on these differences (1). Sex is usually treated as a potential confounder, ignoring whether results apply to both males and females, and excluding the analysis of differences according to sex itself. While there is increasing interest in developing studies to completely integrate the analysis of sex (2), within dermatology, sex perspective is still an opportunity to identify disparities (3) in order to improve equality and efficiency of care. Psoriasis affects 2–3% of the general population. Although men and women are equally affected in terms of prevalence (4), sex differences have been observed concerning prescription, and effectiveness and safety of systemic treatment (5–16). SIGNIFICANCE The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to determine, in a large group of 2,881 patients followed from January 2008 to November 2018, whether sex influences prescription, effectiveness of therapy, or the risk of adverse events. The results show that women were more likely than men to be prescribed systemic therapy. No differences between men and women were found in the effectiveness of therapy. Women were also more likely to experience adverse events, but the difference in risk is small, and does not justify different management. Some studies have shown that men are more frequently treated with systemic and biological drugs than are women, which has been linked to the greater severity of the disease in men (5, 7). Other publications have demonstrated that women and men experience the social and mental impact of psoriasis differently (8, 9). Sex differences are seen in the subjective disease scores for psoriasis, with women achieving worse scores than men, regardless of treatment (6, 10). Various publications have shown that, irrespective of the severity of the disease, women are more prone than men to depressive symptoms, psychological distress and impairment of quality of life (11). Concerning the safety of systemic therapy in psoriasis, several studies indicate female sex as a predictor for discontinuation of biologic therapy due to a higher frequency of side-effects (6, 12, 13). Nevertheless, these studies have limitations, since many are based on drug survival analyses, which may not be a good instrument for measuring the safety of treatments (14). In order to identify possible differences concerning systemic psoriatic therapy used in daily practice care by female and male patients, the aim of this study was to compare prescription, effectiveness and safety between the sexes in the BIOBADADERM cohort. MATERIALS AND METHODS A detailed description of BIOBADADERM has been published previously (15, 16). Established in 2008 as the Spanish prospective cohort of patients with moderate-to-severe psoriasis receiving systemic therapy, it is aimed at describing long-term safety. All consecutive patients in each centre treated with modern (other than classical) systemic drugs are invited to enter the cohort, as well as the next patient who receives a classical systemic drug (acitretin, cyclosporine, methotrexate). Sixteen dermatology departments, distributed throughout the country, participated in this study. This analysis included all prospective patients from January 2008 through November 2018, excluding patients in combination therapy, due to the difficulty of attributing the results obtained to a single drug. Adverse events (AE) were collected using the Medical Dictionary for Regulatory Activities (MedDRA). Patients were contacted at least once a year, although more frequent visits were usual as part of standard care. All AE were included in the database if they were serious or led to a change in therapy or to an unplanned healthcare demand. Serious AE (SAE) were those that were life-threatening, required prolonged hospitalization, caused persistent disability or resulted in death. Drug exposure to systemic therapy was measured from the start of treatment to the date of last administration, or to the censor date in patients who were lost to follow-up. Patients who were lost to follow-up were censored at the last visit to the dermatologist. BIOBADADERM is monthly monitored online, and once a year data is validated by on-site audits. BIOBADADERM was approved by the Hospital 12 de Octubre Ethics Committee (216/07) and patients gave their written informed consent. Study groups and outcomes The main exposure was sex: males and females. In addition, systemic treatment was further divided into classical therapies (acitretin, cyclosporine, methotrexate) and modern therapies, including biologic and small molecules (etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab and apremilast). The main outcomes were treatment prescription, effectiveness and safety. Prescription was considered as the difference in the odds of use of classical compared with modern therapies. Due to the lack of other effectiveness measures, the probability of treatment discontinuation, due to ineffectiveness or remission, under a competing risks scenario, was considered a proxy measure for effectiveness. Safety was measured using relative risks and risk differences for AE. Statistical analysis Descriptive data were expressed as absolute numbers and percentages for discrete variables, and as medians and interquartile ranges for continuous variables. Results between males and females were compared using the Pearson’s χ2 test or Fisher’s exact test for qualitative variables, and the Wilcoxon–Mann–Whitney test for quantitative variables. For multivariable analysis, individual drugs (not overall categories) were included in the analyses. Propensity scores A propensity score (PS) was estimated in order to reduce the selection bias from non-random allocation of treatments in cohort studies. PS was created based on the probability of indication for classical against modern therapies and was obtained by building a logistic regression model, using all variables potentially associated with treatments and outcomes as independent variables (17). PS was incorporated as a confounder in the analysis of all outcomes, except for the analysis of prescription, since the aim of the current study was not to control for the difference in the use of treatments, but to detect it. Missing values analysis Most of the variables analysed had no relevant missing data. Some comorbidities had missing data, most ranging between 4% (e.g. hypertension) and 6% (e.g. chronic liver disease). The highest percentage was for alcohol consumption (23%). Five complete datasets were created by means of chained equations, assuming that missing values were missing at random, using a fully conditional specification model (18). Missing values were imputed using other T individual’s observed variables. Imputed values were examined using iteration to assess convergence and stationarity of each chain. The 5 datasets were analysed using specific regression models for every outcome. Finally, the results of the complete datasets were combined into a single set of estimates using the Rubin rules (19). Prescription A nested case-control design with incidence density sampling was used. Prescription was the outcome and sex was the exposure. For this analysis, a multilevel mixed-effects logistic regression model was built to determine the association between modern systemic therapy and sex. The hospital was considered as a random effect, due to within-centre clustering of patients. Firstly, crude results were obtained with univariate regression analysis, using treatment as outcome, sex as exposure, and demographic characteristics (age, body mass index (BMI), smoking and alcohol consumption), clinical characteristics (disease duration, Psoriasis Area and Severity Index (PASI), type of psoriasis and psoriatic arthritis), comorbidities and previous treatments (number of previous systemic classical treatment, previous phototherapy and treatment order) as independent variables. A backward selection multivariate model was then constructed to adjust for confounders, using variables potentially associated with prescription in the univariate model. Effectiveness Using the cohort design, survival of first drug was measured as a proxy for effectiveness in a competing risk survival scenario. Competing risks regression models were used to compare every specific subhazard ratio (SHR) for ineffectiveness or remission (similarly interpreted to hazard ratios in Cox regression) and cumulative incidence functions (CIF) of discontinuation. AE, remission and ineffectiveness were considered as main competitors, whereas all other reasons for discontinuation (e.g. lost to follow-up, patient’s decisions) were considered as right censoring (20). Subhazard ratios were estimated firstly in crude models, and then built by means of a backward selection multivariate model, using the same potential confounders as in prescription analysis, plus the PS. CIF were represented showing the probability of specific withdrawal over time. Safety Crude and adjusted incidence rate ratios (aIRR) and incidence rate differences (IRD, similarly interpreted as risk differences) were estimated for all AE, SAE, fatal events and each MedDRA system organ class group compared between males and females. For aIRR, a mixed-effects Poisson regression model was used, considering the hospital as a random effect. Age, psoriatic arthritis, specific treatment, cycle order and PS were included in the final model as the main confounders, according to univariate models and previous results (16). Incidence rates of AE per 1,000 patient-years of exposure by period were also described. All analyses were performed using STATA v.14.2 (Stata Corp. (College Station, TX, USA) 2015. Stata Statistical Software: Release 14). A p-value < 0.05 was considered statistically significant. RESULTS A cohort of 2,881 patients with psoriasis treated with systemic therapy was analysed, of which 1,680 (58.3%) were male and 1,201 (41.7%) were female; of the latter, 56% were women of reproductive age (15–49 years). Median PASI at baseline was higher in men (11.2 vs 9, p < 0.0001). Almost all patients had plaque psoriasis, although women had a higher frequency of guttate and palmoplantar pustular psoriasis (p < 0.0001). Twelve percent of the patients had psoriatic arthritis, with no differences according to sex. Other demographic and baseline clinical patient characteristics are shown in Table I. Table I Descriptive baseline demographic and clinical characteristics of psoriatic patients treated with systemic therapy, by sex. Patients included in the BIOBADADERM cohort (2008 to 2018) Characteristics Males (n = 1,680) Females (n = 1,201) Total (n = 2,881) p-value Age, years, median (IQR) 51.8 (42.1–61.6) 51.7 (40.8–62.8) 51.8 (41.6–62) 0.2021 Disease duration, years, median (IQR) 13.9 (6.3–23.6) 13.1 (5.3–25.5) 13.7 (5.8–24.3) 0.5399 PASI, median (IQR) 11.2 (7.2–16.2) 9 (5.1–13.5) 10.2 (6.2–15) < 0.0001 Current and former smoking, n (%)a 712 (53) 451 (46) 1,163 (50) 0.0004 Current and former alcohol consumption, n (%)a 455 (36) 113 (12) 568 (26) < 0.0001 Body mass index, kg/m2, n (%)a < 0.0001 < 18.5 3 (0) 21 (2) 24 (1) 18.5–24.9 354 (27) 365 (39) 719 (32) 25–29.9 530 (41) 281 (30) 811 (36) > 30 411 (32) 270 (29) 681 (30) Plaque psoriasis, n (%) 1,590 (95) 1045 (87) 2,635 (91) < 0.0001 Guttate psoriasis, n (%) 57 (3) 85 (7) 142 (5) < 0.0001 Erythrodermic psoriasis, n (%) 38 (2) 16 (1) 54 (2) 0.0717 Generalized pustular psoriasis, n (%) 10 (1) 13 (1) 23 (1) 0.2016 Palmoplantar pustular psoriasis, n (%) 38 (2) 113 (9) 151 (5) < 0.0001 Annular pustular psoriasis, n (%) 4 (0) 3 (0) 7 (0) 1.0000 Acrodermatitis continua of Hallopeau, n (%) 2 (0) 1 (0) 3 (0) 1.0000 Psoriatic arthritis, n (%) 200 (12) 140 (12) 340 (12) 0.8389 Ischaemic heart disease, n (%)a 60 (4) 17 (2) 77 (3) 0.0004 Heart failure, n (%)a 17 (1) 12 (1) 29 (1) 0.9570 Hypertension, n (%)a 354 (22) 240 (21) 594 (22) 0.5072 Diabetes, n (%)a 189 (12) 119 (10) 308 (11) 0.2275 Hypercholesterolaemia, n (%)a 433 (27) 283 (25) 716 (26) 0.1739 Chronic obstructive pulmonary disease, n (%)a 59 (4) 20 (2) 79 (3) 0.0025 Cancer in last 5 years excluding NMSC, n (%)a 6 (0) 5 (0) 11 (0) 1.0000 Chronic liver disease, n (%)a 116 (7) 37 (3) 153 (6) < 0.0001 Renal insufficiency, n (%)a 24 (2) 13 (1) 37 (1) 0.4060 Hepatitis B virus, n (%)a 77 (6) 34 (4) 111 (5) 0.0090 Hepatitis C virus, n (%)a 43 (3) 16 (2) 59 (3) 0.0248 HIV, n (%)a 16 (1) 2 (0) 18 (1) 0.0015 a Variables with few missing data. IQR: interquartile range; OR: odds ratio; PASI: Psoriasis Area and Severity Index; NMSC: non-melanoma skin cancer; HIV: human immunodeficiency virus. Shaded areas correspond to variables with a p-value <0.05. Most patients (54%) had tried at least one classical treatment prior to entry in the cohort, whereas only 11% had tried modern treatment (biologics or apremilast). Thirty-eight percent of patients had tried previous phototherapy. A majority of patients (53%) had received at least 2 drugs. Regarding both classical and modern therapy, methotrexate was the drug most often used as first treatment (26%), followed by etanercept (15%). Regarding all current and past treatments, methotrexate was also the most frequent (23%). One out of every 2 patients received current modern therapy. Additional information is shown in Table SI1. Prescription Crude analysis in Table II shows that males were not more likely than females to be prescribed modern systemic therapy (odds ratio (OR) 1.03; 95% confidence interval (95% CI) 0.93–1.15). However, when the adjusted odds of prescription were compared, females had a 33% higher chance than males of being prescribed modern therapy (OR 1.33; 95% CI 1.15–1.55). The results were corrected for those significant possible confounders, including age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, chronic obstructive pulmonary disease (COPD), liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, treatment order and previous phototherapy. Table II Prescription and effectiveness models of patients treated with modern systemic therapy, measuring the effect of sex Prescription model Crude OR, (95% CI) p-value Adjusted OR, (95% CI) p-value Females compared with males 1.03 (0.93–1.15) 0.5710 1.33 (1.15–1.55)a 0.0001 Effectiveness model Crude SHR, (95% CI) Adjusted SHR, (95% CI) Ineffectiveness: Females compared with males Remission: Females compared with males 1.14 (0.97–1.33) 0.96 (0.81–1.14) 0.1180 0.6580 1.17 (1.00–1.38)b 1.00 (0.83–1.20)c 0.0550 0.9640 a Corrected for age, risk habits (alcohol consumption and smoking), duration of disease, comorbidities (diabetes, COPD, liver failure), the clinical subtype of the disease (plaque psoriasis and psoriatic arthritis), PASI, number of previous classical systemic treatments, order of treatment and previous phototherapy. b Corrected for number of previous classical systemic drugs, specific treatment and propensity score. c Corrected for PASI, liver failure, number of previous classical systemic drugs, specific treatment and propensity score. SHR: subhazard ratio; cI: confidence interval; OR: odds ratio. Shaded areas correspond to variables with a p-value <0.05. Effectiveness No correlation was found between sex and risk of discontinuing the first treatment due to clinical ineffectiveness, neither crude nor corrected for significant confounders, such as the number of previous classical systemic drugs, specific treatment and propensity score (SHR 1.17; 95% CI 1.00–1.38; p = 0.055). There were also no differences related to suspension due to remission of the disease, neither crude nor corrected for PASI, number of previous classical systemic drugs, liver failure, specific treatment and PS (SHR 1.00; 95% CI 0.83–1.20; p = 0.964) (Table II). Cumulative incidence curves in competing risks of ineffectiveness and remission over time are shown in Fig. 1. No statistical differences (p > 0.05) were observed between males and females. Fig. 1 Cumulative incidence curves of drug withdrawal, by sex. Each line represents the cumulative probability of withdrawal for each specific reason over time. Safety Table III summarizes the differences in the rates of specific AE between males and females. The aIRR of AE was significantly higher in women, including both the overall rate (1.37, 95% CI 1.3–1.44) and the rate of SAE (1.28, 95% CI 1.09–1.51), leading to a risk difference (95% CI) of 232 (198–266) and 16 (5–26) events per 1,000 patient-years, respectively. However, the adjusted incidence rate of fatal AE was slightly lower in women, with a non-statistically significant effect (aIRR 0.55, 95% CI 0.3–1.01). Table III Incidence of adverse events (AE), relative risks and risk differences in specific MedDRA System Organ Class, measuring the effect of sex Type of AE Female (patient-years = 3,894) Male (patient-years = 5,834) Crude IRR, 95% CI Adjusted IRR, 95% CIa Events, n Incidence* Events, n Incidence* IRR p-value IRR p-value IRD, 95% CI All AE 3,056 785 (758–3,056) 3,226 553 (534–3,226) 1.4 (1.37–1.43) < 0.0001 1.37 (1.3–1.44) < 0.0001 232 (198–266) Serious AE 280 72 (64–280) 329 56 (51–329) 1.27 (1.19–1.35) < 0.0001 1.28 (1.09–1.51) 0.0030 16 (5–26) Fatal AE 16 4 (3–16) 33 6 (4–33) 0.69 (0.54–0.88) 0.0027 0.55 (0.3–1.01) 0.0540 –2 (–4–1) Ear and labyrinth disorders 32 8 (6–32) 11 2(1–11) 4.25 (3.21–5.63) < 0.0001 4.09 (2.05–8.17) < 0.0001 6 (3–9) Endocrine disorders 21 5(4–21) 9 2 (1–9) 3.32 (2.4–4.58) < 0.0001 3.42 (1.56–7.48) 0.0020 3 (1–6) Skin and subcutaneous tissue 255 65 (58–255) 213 37 (32–213) 1.76 (1.63–1.9) < 0.0001 1.8 (1.49–2.17) < 0.0001 28 (20–38) disorders Musculoskeletal and CTD 259 67 (59–259) 207 35 (31–207) 1.88 (1.75–2.03) < 0.0001 1.77 (1.47–2.12) < 0.0001 32 (22–40) Nervous system disorders 189 49 (42–189) 139 24 (20–139) 1.97 (1.8–2.15) < 0.0001 1.77 (1.42–2.21) < 0.0001 25 (17–33) Administration site conditions 218 56 (49–218) 174 30 (26–174) 1.82 (1.68–1.98) < 0.0001 1.76 (1.44–2.16) < 0.0001 26 (18–35) Blood and lymphatic system 87 22 (18–87) 72 12 (10–72) 1.74 (1.53–1.97) < 0.0001 1.71 (1.25–2.34) 0.0010 10 (5–15) disorders Gastrointestinal disorders 281 72 (64–281) 227 39 (34–227) 1.76 (1.63–1.88) < 0.0001 1.55 (1.3–1.86) < 0.0001 33 (23–43) Malignant tumours 91 23 (19–29) 90 15 (13–19) 1.5 (1.33–1.69) < 0.0001 1.55 (1.15–2.09) 0.0040 8 (2–14) Surgical and medical procedures 140 36 (30–140) 141 24 (20–141) 1.49 (1.36–1.64) < 0.0001 1.46 (1.15–1.85) 0.0020 12 (5–19) Psychiatric disorders 68 17 (14–68) 67 11 (9–67) 1.54 (1.34–1.77) < 0.0001 1.45 (1.03–2.05) 0.0350 6 (1–11) Infections and infestations 553 142 (131–553) 634 109 (101–634) 1.32 (1.26–1.38) < 0.0001 1.35 (1.2–1.52) < 0.0001 33 (19–48) Eye disorders 34 9 (6–34) 36 6 (4–36) 1.37 (1.13–1.66) 0.0012 1.37 (0.85–2.19) 0.1960 3 (–1–6) Vascular disorders 74 19 (15–74) 74 13 (10–74) 1.41 (1.23–1.61) < 0.0001 1.36 (0.98–1.89) 0.0620 6 (1–12) Congenital, familial and genetic 17 4 (3–17) 18 3 (2–18) 1.41 (1.08–1.85) 0.0126 1.36 (0.7–2.67) 0.3650 1 (–1–4) disorders Reproductive system and breast disorder 32 8 (6–32) 31 5 (4–31) 1.53 (1.25–1.87) < 0.0001 1.49 (0.9–2.46) 0.1230 3 (–1–6) Injury, poisoning and procedural complications 99 25 (21–99) 110 19 (16–110) 1.35 (1.21–1.51) < 0.0001 1.26 (0.95–1.65) 0.1050 6 (0–13) Neoplasms benign, malignant and unspecified 162 42 (36–162) 205 35 (31–205) 1.17 (1.08–1.28) < 0.0001 1.2 (0.97–1.48) 0.0900 7 (–2–14) Respiratory disorders 62 16 (12–62) 79 14 (11–79) 1.15 (1–1.32) 0.0461 1.05 (0.75–1.48) 0.7600 2 (–3–7) Hepatobiliary disorders 82 21 (17–82) 126 22 (18–126) 0.964 (0.86–1.08) 0.5234 1 (0.75–1.32) 0.9740 –1 (–6–5) Renal and urinary disorders 41 11 (8–41) 62 11 (8–62) 0.99 (0.85–1.17) 0.9322 1 (0.67–1.5) 0.9870 0(–4–4) Investigations 206 53 (46–206) 363 62 (56–363) 0.82 (0.76–0.88) < 0.0001 0.81 (0.68–0.96) 0.0100 –9 (–19–0) Metabolism and nutrition disorders 66 17 (13–66) 148 25 (22–148) 0.65 (0.58–0.73) < 0.0001 0.65 (0.49–0.88) 0.0050 –8 (–14 to –3) Social circumstances 4 1 (0–3) 7 1 (1–7) 0.9 (0.54–1.47) 0.6622 0.64 (0.17–2.42) 0.5150 0 (–2–1) Cardiac disorders 31 8 (6–31) 66 11 (9–66) 0.69 (0.58–0.82) < 0.0001 0.62 (0.4–0.95) 0.0280 –3 (–7–1) Immune system disorders 4 1 (0–4) 6 1(0–6) 1.06 (0.64–1.78) 0.8131 NA 1.0000 0 (–1–1) a Corrected for age, psoriatic arthritis, specific treatment, cycle order and PS. CTD: connective tissue disorders; IRR: incidence rate ratio; IRD: incidence rate difference; 95% CI: 95% confidence interval. Incidences per 1,000 patient-years. Shaded areas correspond to variables with a p-value <0.05. DISCUSSION The main findings of this multicentre prospective study with a wide national cohort of psoriatic patients undergoing systemic treatment, are that: (i) women are more likely than men to be prescribed biologics; (ii) effectiveness seems to be similar in both groups; and (iii) AE are more common in women and associate with a different profile to that of men. Although researchers usually keep in mind the role that sex can play as a potential confounder, these findings highlight the fact that analysing results by sex itself is valuable. Concerning psoriasis severity, men had more severe disease at baseline (median PASI 11.2 vs 9), as reported by other studies. Of note, only 12% of the patients in the current cohort had psoriatic arthritis (PsA), with no differences between men and women. Although wide-ranging prevalence estimates of PsA in patients with psoriasis have been reported in the literature, a recent meta-analysis found a prevalence of 22.7% among European patients (21). This difference could be due to real differences in prevalence between Spain and other countries. It could also be related to an information bias, due to lack of assessment of arthritis symptoms during patients’ follow-up, resulting in under-diagnosis of PsA. Another possible reason is the exclusion of patients in combination therapy, since good control of both cutaneous psoriasis and PsA often requires multidrug therapy. Nevertheless, the prevalence in men and women was exactly the same; hence PsA is unlikely to explain the disparities found in prescription and safety. Regarding prescription, this study found that women have a 33% higher probability of being treated with a modern drug (mostly biological therapy) than do men, once confounding factors are taken into account, including disease severity, which tends to be greater in males. A possible reason may be that, as shown in other studies, women tend to subjectively perceive a higher severity of the disease (6, 11, 22, 23), which could translate into higher expectations and demand for modern therapy (24). It is also possible that dermatologists tend to avoid using classical systemic drugs in young fertile and pregnant women because of their potential adverse effects on pregnancy. A sensitivity analysis (Table SII1) was performed to evaluate the association between age and prescription-effectiveness of modern therapy, dividing the population into 2 groups: 20–40 years and > 40 years of age. The odds ratio (OR) of prescription was similar to that of the whole population, suggesting that age does not influence prescription in women. Hägg et al. (5, 7) analysed the Swedish national registry of systemic treatments in psoriasis (PsoReg) to describe the time to prescription of a biologic. They found that 63% of patients treated with biologics were male. However, time to biologic prescription was similar in males and females when confounding factors were taken into consideration (age, BMI, presence of arthritis and PASI). More common prescription in males was attributed to men with more severe psoriasis. The current study included more relevant potential confounders, such as risk habits, comorbidities or previous classical systemic treatments, which could explain the different results. It is also possible that sex differences in prescription vary across countries. Effectiveness was measured using drug survival as a proxy measure, as the current dataset and study design preclude better effectiveness outcomes from being used. Although this method has some drawbacks (14), the current study aimed to minimize them by selecting only survival for specific outcomes in a competing risk scenario, and including the drug in the model. In terms of suspension due to remission or ineffectiveness, no significant differences associated with sex were found. Warren et al. (25) analysed the British Association of Dermatologists Biologic Interventions Register (BADBIR), finding that female sex was associated with reduced odds of achieving ≥ 90% improvement in PASI at 6 and 12 months. However, this was estimated in a multivariable model, in which sex was not being studied as the main exposure, thus it should be interpreted with caution (26). Similarly, Richter et al. (27) identified male sex as a positive predictor of longer adalimumab survival in psoriasis, and Pogácsás et al. (28) observed more long-term survival of TNF-alpha inhibitors and ustekinumab amongst men in a Hungarian cohort. Given the differences in methodologies, further prospective studies should be carried out to measure the impact of sex on the effectiveness of systemic therapies. It would also be useful if randomized clinical trials (2) and systematic reviews (29) provided results by sex, as mentioned previously. Although the vast majority of cases (91%) were plaque psoriasis, the current study aimed to rule out the effect of the specific type of psoriasis in prescription and effectiveness of treatment. Since guttate psoriasis was the second most common type of psoriasis (5%), we carried out a sensitivity analysis (Table SIII1) comparing patients with only plaque and guttate psoriasis vs all patients, finding similar results in both groups. Finally, a 37% higher rate of overall AE and 232 more AEs per 1,000 person-years was found in females. Adverse events were higher in women in all system groups of disease, except in investigations, metabolism, and nutrition disorders and cardiac disorders. This is striking, since women are treated with biological therapy more often than men, rather than classical drugs, and we would expect to find a greater risk of AE in the latter, in contrast to the newer and more targeted biologics. This could be related to the fact that, as mentioned above, women tend to perceive a higher severity of the disease and demand a more intensive follow-up, which could translate into a higher rate of self-reporting of AE. However, this needs to be interpreted with caution, since serious AE were also more frequent in women than men, suggesting that women are indeed more likely to develop AE. The BioCAPTURE registry described that women were less satisfied and experienced AE more frequently than did men (6). Di Cesare et al. (30) found that female sex itself was a risk factor for acute infective events in a cohort of patients with stable chronic plaque psoriasis. Similarly, Zweegers et al. (11) observed that female sex was a predictor for discontinuation of adalimumab, etanercept and ustekinumab due to AE. Similarly, in a recent systematic review, Mourad et al. (31) identified female sex as a predictor of biologic withdrawal owing to AE. An accurate description of safety in women was compiled in the current study, as the study cohort was specifically designed to describe and collect AE, and the current results align with those in the literature. Propensity scores were used to avoid prescription bias. Previous studies have shown that using survival as a proxy outcome for safety can be misleading (14). Study strengths and limitations The main strength of this study is that it analyses a large multicentre prospective cohort formed by patients treated in daily practice care, with long follow-up times. It also comprises a relatively large number of different hospitals throughout the country, where quality of data is constantly monitored. Although residual confounding cannot be totally ruled out from observational studies, a large number of variables were collected that allowed us to control the effect of potential confounders. With the same purpose, the use of propensity scores, when appropriate, helped us to avoid prescription bias. Its limitations are the usage of drug survival as a proxy for effectiveness and the lack of information regarding specific variables of interest, such as the level of satisfaction with the treatment or the benefits of treatment in terms of quality-adjusted life years. As mentioned previously, the current study excluded patients in combination therapy due to the difficulty of attributing the results to a specific drug, and this may have acted as a limitation. Conclusion These findings indicate that there may be a sex distinction in prescription of biological drugs in favour of females. Effectiveness, measured as drug survival, seems to be similar in both sexes, either in terms of suspension due to remission or ineffectiveness. We have found that women have a greater risk of developing serious and global AE. Despite the contrast in prescription and safety, these differences are relatively small and should not prompt a different follow-up and management between males and females. These results emphasize the need to consider sex as a valuable factor in psoriasis systemic therapy decision-making in routine practice care. They also highlight the importance of analysing and presenting results of studies by sex. ACKNOWLEDGEMENTS This work was conducted within the BIOBADADERM Study Group. The following members participated in acquisition of data and review of the manuscript: Esteban Daudén, Mar Llamas-Velasco (Hospital Universitario de la Princesa); Gregorio Carretero, Jaime Vilar-Alejo (Hospital Universitario de Gran Canaria Dr. Negrín); Raquel Rivera, Carmen García-Donoso (Hospital Universitario 12 de Octubre); Carlos Ferrándiz, José Manuel Carrascosa, Ferrán Ballescá (Hospital Universitari Germans Trias i Pujol); Pablo de la Cueva (Hospital Universitario Infanta Leonor); Isabel Belinchón (Hospital General Universitario de Alicante); Fran J. Gómez-García, Rafael Jiménez (Hospital Universitario Reina Sofía); Enrique Herrera-Ceballos, Enrique Herrera-Acosta (Hospital Universitario Virgen de la Victoria); José Luis López-Estebaranz, Diana Patricia Ruiz-Genao (Fundación Hospital de Alcorcón); Marta Ferrán Farrés (Hospital del Mar, Parc de Salut Mar de Barcelona); Mercè Alsina (Hospital Clinic de Barcelona); Ofelia Baniandrés, Lula Nieto (Hospital General Universitario Gregorio Marañón); José Luis Sánchez-Carazo (Hospital General Universitario de Valencia); Antonio Sahuquillo-Torralba, Rafael Botella-Estrada, Conrad Pujol Marco (Hospital Universitario La Fe de Valencia); Lourdes Rodríguez Fernández-Freire (Hospital Universitario Virgen del Rocío de Sevilla); Almudena Mateu Puchades (Hospital Universitario Dr. Peset), Ángeles Flórez Menéndez, Laura Salgado, Beatriz González Sixto (Complexo Hospitalario Universitario de Pontevedra); Noemí Eiris (Complejo Asistencial Universitario de León); Ignacio García-Doval, Miguel Ángel Descalzo Gallego, Marina de Vega Martínez (Fundación Piel Sana AEDV). The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall). Collaborating pharmaceutical companies were not involved in the design and conduct of the study; collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication. The authors are grateful to Paloma Hernández Fernández for copyediting the manuscript. The patients in this manuscript provided written informed consent to publication of their case details. Conflicts of interest. GC has been reimbursed by Janssen, Abbvie, Novartis, Pfizer, MSD and Celgene for advisory service and conference. RR acted as consultant and/or speaker for and/or participated in clinical trials as IP for Abbvie, Almirall, Celgene, Janssen, Leo Pharma, Lilly, Novartis, MSD and Pfizer-Wyeth. CF has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Amgen, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Merck Sharp & Dohme, Novartis Pfizer and Almirall. ED acted as consultant for Abbott, Amgen, Astellas, Centocor Ortho Biotech Inc, Galderma, Glaxo, Jansenn-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene, received honoraria form Abbott, Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD, Celgene, participated in a speakers bureau for Abbott, Pfizer, MSD and Janssen and received grants from Pfizer, Abbott, Janssen and MSD. PdlC acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, UCB, Biogen, Celgene, Amgen, Sandoz, Sanofi and Leo-Pharma. IB acted as a consultant and/or speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including Janssen Pharmaceuticals Inc, Almirall SA, Lilly, AbbVie, Novartis, Celgene, Biogen Amgen, Leo-Pharma, Pfizer-Wyeth, and MSD. EH-A has served as consultant and/or speaker with Leo Pharma, Novartis, Janssen, Lilly, Celgene y Abbvie. DR-G has been reimbursed by Pfizer, Janssen, Celgene, Abbvie, Novartis and LeoPharma for advisory services and conferences. MF has participated as speaker and/or advisor for Janssen, Lilly, Novartis, Pfizer, MSD, Abbvie Celgene and Almirall. MA gave expert testimony for Merck-Schering Plough, Pfizer, Janssen, Novartis and Abbott. OB-R acted as a consultant and/or speaker for Janssen-Cilag, AbbVie, Pfizer, Novartis, Lilly, Celgene, Leo Pharma and Almirall. JLS-C participated as AB from Janssen, Novartis and Leo Pharma. AS-T has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. LR acted as a consultant and speaker for Janssen-Cilag, AbbVie, MSD, Pfizer, Novartis, Lilly, Almirall, Celgene and Leo-Pharma. JV-A participated as AB from Janssen, Novartis, AbbVie, Almirall and Celgene. CG-D participated as AB from AbbVie, Almirall and speaker for Janssen, Lilly and Celgene. JMC has participated as speaker and/or advisor for Celgene, Janssen, Lilly, Novartis, Leo Pharma, Pfizer, MSD, Abbvie, Biogen Amgen. ML-V acted as a consultant and speaker and participated in clinical trials for Janssen-Cilag, AbbVie, Celgene, Pfizer, Novartis, Lilly, Almirall and Leo-Pharma. EH-C has served as a consultant and/or speaker for and/or participated in clinical trials as IP and sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. JLL-E participated as AB and received educational grants from Janssen, Abbvie, MSD, Lilly, Novartis, LeoPharma, Pfizer. RB-E has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. CP-M has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Celgene, Janssen-Cilag, LEO Pharma, Lilly, Novartis and Pfizer. IG-D received travel grants for congresses from Abbvie, MSD and Pfizer. 1 https://doi.org/10.2340/00015555-3711	Fatal	ReactionOutcome	CC BY-NC	33269405	18,973,641	2021-01-04
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breast cancer'.	NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU. Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months. In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. 284-10 (03.05.2018). Introduction In women, metastatic breast cancer and gynecological malignancies are among the most frequent causes of cancer death. In 2018, there were an estimated 2,088,849 new cases of breast cancer and 626,679 deaths, 569,847 new cases of cervical cancer and 311 365 deaths, and 295,414 new cases of ovarian cancer and 184,799 deaths worldwide. [1] Despite rising overall incidence, mortality rate has steadily decreased owing to early detection and improvements in the therapeutic management of these patients. However, although the development of new drugs, vaccines, and systematic screening programs has improved patients’ outcomes, effective measures to successfully treat metastatic cancer are still missing. With the advent of molecular diagnostics, cancer treatment entered a new era. New techniques of sequencing DNA such as comprehensive genomic profiling (CGP) and hotspot next generation sequencing (NGS) provide tools for deciphering complete genes and later entire genomes at unprecedented speed [2]. These new approaches led to the development of a novel cancer treatment movement, known as precision medicine. By selecting the most effective treatment based on the molecular characteristics of tumor tissues or some other biologic parameters of the malignant disease, precision medicine aims to offer personalized treatment concepts to cancer patients with limited standard of care options. Molecular therapeutic agents (MTA) targeting individual actionable molecular alterations have been successfully developed in the past few years, showing the positive impact of using molecular-based therapy on the cancer patients’ outcome [3–6]. These include the use of growth factor receptor 2 antibody trastuzumab in breast cancer, a tyrosine kinase inhibitor imatinib in myelogenous leukemia associated with the BCR-ABL fusion gene and EGFR tyrosine kinase inhibitors in lung carcinomas [7, 8]. Breast and gynecological cancers constitute a heterogeneous group of malignant diseases associated with multiple genetic alterations [9–11]. In the past few years, a growing number of molecular markers in breast cancer, for example, have been investigated and some of them are now well-established as reliable predictors of prognosis and response to tumor therapy (Fig. 1a). Moreover, many different targeted therapies have been approved for use in breast cancer treatment (Fig. 1b). The recent approval of the PIK3CA specific inhibitor alpelisib has been the most recent example of targeted agents moving into routine care. [12] Treatment with alpelisib was shown to prolong PFS by more than 6 months compared to the control arm. [13]Fig. 1 Predictive factors (a) and treatment-relevant genetic alterations (b) in metastatic breast cancer, German Gynecological Oncology Group. In 2018, AGO was the first international guideline-commission to make recommendations regarding precision medicine in breast cancer. (http://www.ago-online.de) [14] In gynecologic malignancies, MTAs have also been successfully implemented into clinical care. For example, early data from a clinical phase II trial focusing on BRCA-mutated ovarian cancer showed that olaparib as maintenance treatment significantly improved progression-free survival (PFS) in relapsed platinum-sensitive ovarian cancer [15]. In 2018, these data could be transferred to the first line setting when treatment effects of the SOLO1 trial were presented [16]. Due to an impressive PFS improvement and a 70% lower risk of disease progression or death with olaparib compared to placebo, this effect led to the incorporation of PARP inhibitors into the primary treatment of ovarian cancer in 2019 [17]. However, when it comes to other gynecologic malignancies such as endometrial cancer, the development of MTA is delayed in comparison to other malignancies. By detecting potential actionable pathways using molecular diagnostics, it is also possible to assess and treat various cancer types. For example, the ERBB2/PIK3/AKT/mTOR pathway is known for its relevance in breast cancer, but recently a relevant actionable mutation from the same pathway, PIK3R1W624R was also identified in ovarian cancer [18]. Another study suggested that some subtypes of cervical cancers may also benefit from existing ERBB2/PIK3/AKT/mTOR targeted agents [19]. With the rising number of MTAs and considering the heterogeneous molecular profiles of breast cancer and gynecological malignancies, it is reasonable to expect that patients with these malignancies could potentially benefit from implementation of precision oncology based on comprehensive genomic profiling (CGP) into clinical care. Promising early data for such malignancies has been presented in multiple trials. In breast cancer, many reports of such driver alterations have emerged in the past few years, suggesting that patients could profit from precision medicine and targeted therapies [20]. For example, in the SAFIR01 multicenter prospective trial, data of precision medicine benefitting breast cancer patients were presented. 9 out of 43 patients (21%) responded to the recommended targeted therapy with a stable disease lasting over 16 weeks [21]. In ovarian cancer, multiplatform molecular profiling, conducted in a commercially available profiling center, led to a significantly longer post-profiling survival in patients, who were treated with profile-guided targeted agents, in comparison to the control group [22]. With the technical advances in molecular diagnostics and the continuous approval of many targeted therapies, the growing field of precision medicine is constantly expanding and requires optimization. Considering the complexity of precision medicine in oncology, it was reasonable to create a molecular tumor board (MTB) to leverage the knowledge of the many different disciplines involved in oncological treatment and to provide optimal treatment recommendations. In this manuscript, first experiences of the Comprehensive Cancer Center (CCC) LMU Munich Molecular Tumor Board are presented. The aim of this project was to retrospectively measure the impact of MTB discussions and recommendations made by a multidisciplinary tumor board on outcome of patients with breast and gynecological cancers progressing under standard treatment. Detailed information including data on patient characteristics, diagnostic and treatment recommendations, implementation of the recommendations, and outcome of treated patients with breast and gynecological cancers (ovarian, endometrial, cervix, and other type of cancer) are presented. Materials and methods All patients reported here were discussed in the local MTB, which reviewed clinical cases and the respective tumor profiles with the associated actionable alterations. The final result of each MTB case discussion was a report, focused on NGS data and diagnostic and potential diagnostic, and therapeutic alternatives. Thereby, the MTB presented itself as a multidisciplinary team (MDT), which comprised clinical oncologists, pathologists, molecular pathologists, genetic counselors, bioinformaticians, and scientists with expertise in genetic and tumor profiling in diverse cancers. MTB-meetings were held every 2 weeks with the purpose of interpretation and/or translation of the molecular diagnostics’ results into diagnostic and/or treatment recommendations. All patients’ cases were first presented at organ-specific gynecology tumor boards by a team of experienced gyneco-oncologists, who reviewed all the clinical course of every individual patient and discussed if patients were eligible for a MTB discussion. Apart from recent tumor material, recent radiology images and other diagnostic tests were also required for the interdisciplinary setting of the MTB. All treatment recommendations were supported by levels of evidence by using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). The process from enrolling the patient into the study till receiving a recommendation by the MTB is shown in Fig. 2.Fig. 2 MTB, from suggestion to conclusion Patients and patient informed consent All patients discussed (n = 95) were included in the prospective single-center case study, “The informative Patient”, launched in March 2017 at the LMU University Hospital, Munich as a Munich-site part of the DKTK (German Cancer Consortium) program. All enrolled patients suffered from metastatic breast or gynecological cancer which had progressed after at least one line of prior standard treatment and who had no longer access to curative treatment. Prior to inclusion, all participants signed an informed consent that they were informed about potential and limitations that molecular diagnostics could offer for treatment selection and for analysis of their data, further discussion of their case by a multidisciplinary MTB, as well as for collecting follow-up data on the course of disease for research purpose (including requesting patient data from other physicians and institutions). The intention-to-treat (ITT) population consisted of 100 patients. Eventually, five patients were excluded, because of death prior to a treatment recommendation or withdrawal of consent. The data here are based on the results of an ITT population of 95 patients. Molecular pathology Molecular analyses were performed at the Institute of Pathology of the LMU. Appropriate tissue regions were selected histo-morphologically from formalin-fixed paraffin embedded (FFPE)- or fresh frozen tissue. Moreover, liquid biopsies (blood, liquor) were included. In only four patients, analysis had to be repeated due to material constraints. Targeted NGS was performed with the Oncomine Comprehensive Cancer v.3 Panels (Agilent) thereby screening for changes in 161 genes on DNA (SNV, MNV, small ins, del, indels, CNV) and RNA (gene fusions) level. DNA and RNA were isolated using Qiagen's GeneRead DNA FFPE- or RNeasy FFPE-kits, respectively. Nucleic acids (NA; DNA, and RNA) from liquid biopsies were prepared by utilization of the QIAamp Circulating Nucleic Acid Kit. Subsequently, library preparation as first step of NGS was generated by employing Ampliseq Library Plus-, Ampliseq cDNA synthesis-, Ampliseq CD index, Ampliseq Equalizer- together with Ampliseq Comprehensive v3-kits (all Illumina) or DNA- and RNA-Oncomine Comprehensive Panels v3 and Ion AmpliSeq Library-, IonXpress Barcode Adapter-, Ion Library Equalizer-kits together with Ion Chip kits (mostly 550) (all Thermo Fisher), following for each step the respective user manuals. Libraries were run on an Ion Torrent GeneStudio S5 Primer (Thermo Fisher) or Illumina 500 Next Seq (Illumina) NGS machine. Analysis of results was performed with either the Ion-Reporter System (Thermo Fisher) followed by further variant and quality interpretation with a self-made excel tool or annotating VCF-files using wAnnovar (http://wannovar.wglab.org/) [23] together with the self-made python-script PathoMine filtering for clinically relevant mutations. Mutations were judged as relevant on the basis of the key 'interpretation' given in ClinVar [24]. Alterations were confirmed with the Integrated Genomics Viewer (IGV, Broad Institute). The resulting molecular pathological dataset together with data from immunohistochemistry, fluorescence in situ hybridization (FISH), and histo-morphology became part of a comprehensive pathological report which was sent out to the MTB. Data assessment For this analysis, electronic medical records were reviewed for patient characteristics and follow-up. If needed, medical oncologists, gynecologists, and general practitioners were contacted in order to collect follow-up data on treatment course and patient status. Patient characteristics were summarized using descriptive statistics. Follow-up of clinical outcomes was performed to track tumor response to recommended therapies and analyzed by measuring progression-free survival (PFS) of patients, who received the recommended treatment. PFS was calculated from the first day of treatment with the recommended in- or off-label targeted drug until the date of disease progression or death, whichever occurred first, analogous to the Johns Hopkins MTB study and to the Von Hoff et al. study [25]. In order to evaluate the benefit of the treatment recommendation, we then calculated the PFS ratio (PFSr) by comparing the PFS of the recommended treatment and the PFS of the previous therapy of the patients. Cut-off date for data analysis was August 1st, 2019. Results Patient characteristics From March 2017 through March 2019, a total of 95 cases were submitted to the MTB. All patients (n = 95) were females, had an underlying malignant condition, suffered from metastatic disease, and had experienced disease progression under standard treatment. Patients with implemented therapy recommendations had received a median of five (range 2–6) prior therapies for metastatic cancer. The median age at time of the initial MTB presentation was 52 years (range 19–82 years). As shown in Fig. 3, the most frequent tumor type was breast cancer (n = 64, 68%), followed by ovarian cancer (n = 19, 20%). The majority of patients with breast cancer had triple-negative (ER, PR and HER2 negative; n = 30; 46.9%), followed by estrogen receptor (ER) -positive and/or progesterone receptor (PR) -positive, human epidermal growth factor receptor 2 (HER2) -negative (luminal-like) (n = 28; 43.8%), or HER2 positive, ER-negative, PR-negative disease (n = 5; 7.8%) at the time of the MTB case discussion; one patient (1.6%) had triple-positive disease (ER positive and/or PR positive, HER2 positive).Fig. 3 Distribution of the cases discussed at the MTB meeting by tumor entity (n = 95) Characteristics of patients with a molecular profile are reported in Table 1.Table 1 Patient characteristics Covariables Median age at diagnosis 47 years (range 12–80) Age at diagnosis < 30 5 (5.3%) 30–39 27 (28.4%) 40–49 21 (22.1%) 50–59 30 (31.6%) 60–69 8 (8.4%) ≥ 70 4 (4.2%) Median age at MTB case presentation 52 years (range 19–82) Age at MTB case presentation < 30 2 (2.1%) 30–39 19 (20.0%) 40–49 20 (21.1%) 50–59 28 (29.5%) 60–69 18 (18.9%) ≥ 70 8 (8.4%) Molecular profiling Molecular tests using NGS were performed for all 95 patients. Out of the set of mutations from the molecular pathological NGS-analysis, actionable mutations were defined as those matching or informing the use of available targeted agents. Four patients had tumor sequencing performed twice during the course of disease. 81 (85.3%) patients had suitable tissues for multimodal molecular profiling (NGS). All in all, 103 molecular alterations were identified in 55 cases (57.9%). The median number of alterations observed in each sample was one (range 0–6). Out of the 55 patients, 41 (43.2%) had an actionable mutation, which the board reviewed as a potentially targetable. No genomic alterations in the 161 investigated genes were found in 40 (42.1%) analyses, in 14 (14.7%) of which the molecular diagnostics test was technically not successful because of poor DNA quality or insufficient material quality. Although five (5.3%) patients had an actionable mutation, they did not receive a therapy recommendation because of co-morbidities, not meeting trial inclusion criteria, or other requirements for receiving a specific targeted therapy. We discovered mutations in over 30 different genes. Among the patients tested, the most common alterations were as follows: PIK3CA mutation (13/95; 13.7%); ERBB2 mutation (10/95; 10.5%); KRAS mutation (9/95; 9.5%), and CCND1 mutation (9/95; 9.5%). Incidences of genomic alterations by gene and the distribution of molecular alterations by tumor type are shown in Fig. 4.Fig. 4 Frequency of genomic alterations for the different tumor entities (n = 95) Recommendations Among the 55 (57.9%) patients with at least one molecular alteration identified, 41 patients (43.2%) had an actionable alteration, whereas 14 (14.7%) had only non-actionable variants. Eventually, this resulted in 15 diagnostic and 49 treatment recommendations for 45 patients (47.4%). Multiple recommendations were adjusted for 20 (21.1%) patients (multiple recommendation principle). Six patients received a conditional recommendation, which required specific further diagnostics, two of which resulted in a treatment recommendation. Diagnostic recommendations Out of 15 diagnostic recommendations, 10 were pursued. In seven (7.4%) cases, extended genetic analyses were recommended and eventually six (6.3%) of them were performed. Re-biopsies were recommended in 14 cases, when the initial diagnostic tests were technically not successful, which we did not include in the evaluation of the final results. Therapeutic recommendations As shown in Fig. 5, 36 (37.9%) patients were given a therapy recommendation, 14 (14.7%) of whom received more than one treatment suggestion, as their tumor molecular profile revealed more than one actionable mutation. Two (2.1%) patients were excluded from the evaluation of the clinical outcome, as they received the recommended therapy in the period between NGS analysis and MTB treatment recommendation.Fig. 5 Treatment or diagnostic recommendations. Note, all numbers do not add up because some patients are counted in more than one category (e.g., had an actionable alteration for a treatment recommendation and also for diagnostic recommendation or received more than one treatment/ diagnostic recommendation). a Diagram representing the outcome of the molecular diagnostic testing (n = 95). b Breast cancer patients. c Gynecological cancer patients Overall, 9 of 34 therapeutic recommendations were pursued. Of note, in the present cohort, no patient pursued the recommended enrollment in a clinical trial. In-label therapy recommendations were implemented in five cases, whereas off-label recommendations were implemented in four patients. The most common reasons for non-administration of MTB-recommended therapy were deterioration of patients’ physical health condition, early death, no access to the recommended drug therapy, declined reimbursement applications by payer, or patient decision (see Table 2).Table 2 Recommendations (Note, some patients received more than one diagnostic and/or treatment recommendation.) BC GC Patients with min. 1 recommendation No No Diagnostic 8 7 Therapeutic 27 7 No treatment recommendation 30 20 Conditional recommendation 3 3 Referral to organ board 1 Diagnostic recommendations Extended genetic analysis 3 4 PD-L1 Test 2 HR-Status 1 1 Other 5 3 Patients with diagnostic recommendations (n = 15) Implemented 6 4 Non-implemented 2 3 Treatment recommendations Targeted therapy 32 5 Trial inclusion 8 2 Checkpoint inhibition 1 1 Patients with treatment recommendations (n = 36) Implemented 7 1 Non-implemented 22 6 Clinical outcome All patients were included in the registry after multiple standard of care treatments. Out of nine (9.5%) patients following therapy recommendation, 4 (4.2%) showed a state of partial remission or stabilization lasting more than 16 weeks, including two of them receiving off-label therapy recommendation. Comparing PFS of the recommended therapy with the PFS of the previously received systemic treatment, we estimated that four of nine responders receiving MTB-recommended therapies displayed a progression-free survival (PFS) ratio (PFS2/PFS1; PFSr) > 1.3, showing the relevance of the suggested therapies. Two patients responded with an ongoing PFSr. Figure 6 details the actual comparison of PFS on implemented recommended treatment versus PFS on the patient’s last prior treatment.Fig. 6 Comparison of PFS of previous line of therapy (PFS1) and implemented therapy recommendation (PFS2). PFS the period of time between the start of treatment till disease progression/ death More information about the outcome of responding patients is shown in Table 3.Table 3 PFS ratio (PFSr) = ratio of patients’ PFS on the implemented recommended therapy (PFS2) (in this case the recommended in- or off-label targeted drug) to their PFS on the most recent previous line of therapy (standard of care) (PFS1) # Tumor entity Treatment Label PFS2 (weeks) PFS1 (weeks) PFSr 1 Breast Everolimus In 14 81 0.17 2 Breast Everolimus In 12 55 0.22 3 Breast Exemestan + Everolimus + Trastuzumab Off 4 8 0.50 4 Breast Everolimus In 13 13 1.00 5 Breast Pazopanib Off 12 6 2.00 6 Breast Lapatinib In 18 3 6.00 7 Breast Palbociclib In 21 13 1.62 8 Breast Pembrolizumab Off 59 5 11.80 9 Cervix Temsirolimus Off 32 38 0.84 PFSr PFS2/PFS1 See Appendix for details of identified actionable mutations and corresponded treatment recommendations made by the MTB. Discussion We evaluated the clinical consequences of actionable genetic alterations (by NGS) in 95 patients with metastatic breast cancer and gynecological malignancies, part of a pilot monocentric patient registry with the purpose of generating real-world data. Forty-one patients (43.2%) had at least one actionable molecular aberration. The total number of patients with a drug-targetable alteration was 34 (35.7%). Overall, 9 of 34 patients (9.5% of all) received the recommended drug treatment. In a small, but significant group of patients, four out of nine with implemented therapy recommendations (44.4%) experienced a clinical benefit (PFSr > 1.3) lasting over 16 months, a result similar to the one shown by Jameson et al. in cases of patients with metastatic breast cancer, who received personalized therapy recommendations based on multi-omic molecular profiling [26, 27]. Precision medicine offers not only personalized treatment concepts for patients, but also helps us optimize diagnostic and treatment options by identifying biomarkers that are linked to response and resistance to immunotherapy. For instance, in the past few years, the problem of resistance to endocrine therapy has been a point of research. Recently, the key role of the acquisition of ligand-independent ESR1 mutation in breast cancer as a common mechanism of resistance to hormonal therapy was discovered [28]. So far, the precision medicine movement is controversial and has sparked multiple debates. On the one hand, the SHIVA trial (2015), one of the first randomized investigation of precision therapy, was negative for its primary endpoint (progression-free survival [PFS]), as no statistically significant difference in PFS between patients receiving molecularly targeted agents and the control arm was demonstrated [29]. On the other hand, studies recruiting large number of patients, such as MOSCATO 01 (2017) and ProfiLER (2017), suggested that high-throughput genomic analyses (i.e. next-generation sequencing, comprehensive genomic profiling) improve clinical outcome in patients with advanced cancers. However, this approach has only been proven to be beneficial to a small subset of patients so far [30, 31]. As shown in Table 4, studies focusing on precision medicine show different, contradictory results. While in some studies more than 20% of the enrolled patients received the recommended according to molecular profiling treatment, in others the number of patients treated remains very low. These results suggest the need for large data collections in order to improve selection criteria and identify markers that discriminate patients that might benefit most from precision medicine.Table 4 Overview of studies focusing on molecular profiling Author/Study Tumor entity Enrolled patients (n ) MP patients Actionable alterations Implemented therapies—n (% of enrolled) Results Le Tourneau et al. (SHIVA) [29] Solid tumors 741 496 (67%) 293 (40%) 96 (13%) No significant difference in PFS (PFS: 2.3 vs 2.0 p = .41), hazard ratio for death or disease progression, 0.88 (95% CI 0.65–1.19) Stockley et al. (IMPACT/COMPACT) [45] Solid tumors 1893 1640 (87%) 187 (10%) 84 (5%) ORR: 19% in genotype-matched group vs 9% in unmatched group, p = 0.61 Massard et al. (MOSCATO-01) [30] Solid tumors 1035 843 (81%) 411 (40%) 199 (24%) ORR: 11%, SD 52%, PFSr > 1.3: 63/193 (33% of all treated patients or 7% of all enrolled patients) Trédan et al. (PROFILER) [31] Solid tumors 2579 1980 (77%) 1032 (40%) 163 (6%) ORR: 0.9% of all patients Rodon et al. (WINTHER) [46] Solid tumors 303 303 (100%) 25 (89%) 107 (35%) PFSr > 1.5: 22% of the patients with MP-based treatment Hoefflin et al. [47] Solid tumors 198 n.a 104 (53%) 33 (17%) PR: 11/33 (33.3% of all treated patients or 5.5% of all enrolled patients) SD: 8/33 (24.2% of all treated patients or 4% of all enrolled patients) André et al. (SAFIR01/UNICANCER) [21] Breast cancer 423 299 (71%) 195 (46%) 55 (13%) ORR:4 patients had a partial response and 9 had SD > 16 weeks (3% of all patients) Parker et al. [27] Breast cancer 43 43 (100%) 40 (93%) 17 (40%) 7 patients (41% of all treated patients or 16% of all enrolled patients) achieved SD or PR MP molecular profiled, PFS progression-free survival, ORR overall response rate, SD stable disease, PR disease progression, n.a. not available Although molecular targeted agents themselves are more precise than standard cytotoxic agents, clinical evidence for a significant better outcome associated with MTAs is still missing, as the access to targeted therapies remains limited, making collecting data regarding their efficacy difficult. In order to achieve their implementation in clinical care, a re-assessment of the standards of evidence sufficient to prove the benefit of precision cancer therapies is needed [32]. New evidence suggests that appropriately conducted real-world data studies have the potential to support regulatory decisions in the absence of RCT data [33]. Based on initial results of the CCC LMU Munich, patients of various tumor entities benefit from extended molecular diagnostics and their implementation in clinical care [34]. Recently, many studies have described the positive effect of MTB case discussions for particular groups of patients with advanced solid cancers. However, there is not enough evidence for the utility of MTB decisions for patients with breast and gynecological malignancies. The world of precision medicine is constantly evolving, and new targeted therapies are being developed and approved, enabling more and more patients (with up to this point of time not actionable mutation) to receive targeted therapies. For example, in spring 2019, the Food and Drug Administration of the USA (FDA) approved the PIK3CA inhibitor alpelisib in combination with endocrine therapy for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. The availability of this drug after start of the Managed Access Program in our clinic could have resulted in five further therapy recommendations in our MTB cohort, showing the need of identifying such alterations in cancer patients. The rising number of active targetable mutations affects the complexity of the results, making their interpretation a challenge for many oncologists. In 2014, Gray et al. conducted a study, which evaluated cancer physicians’ ability of using multiplex tumor genomic testing and showed that many physicians lack confidence in interpreting complex genomic test results as well as in incorporating them into practice [35]. Thus, we see great potential in establishing the combination of molecular diagnostic tests and a subsequent case discussion by a multidisciplinary molecular board team not only as a routine for cancer patients but also as a training platform and a knowledge-expanding approach for oncologists to help guide their decisions. However, precision oncology faces some challenges, which delay its widespread translation into clinical practice. Critics of the incorporation of NGS and similar methods into clinical practice express following concerns: First, the significant cost of molecular diagnostics and targeted drugs is still a great disadvantage. While prices of next-generation sequencing technologies are dropping from about $3 billion in the year 2000 and to $5000 today, the selection of molecular targeted agents is still enormously expensive [36]. As the price of precision medicine is still rather high for most patients, it is now crucial to also evaluate its cost-effectiveness in order to support its translation into clinical practice, for example in the setting of clinical trials and research programs [37]. Second, logistical problems causing limited access to targeted drugs and clinical trials for biomarker-positive patients represent another major problem. This is mainly due to the absence of reimbursement for drugs beyond their labelled indication. As a consequence, in order to receive the required, often off-label drug, patients need to be enrolled within active clinical trials or are required to cover the costs themselves or to file an application for reimbursement by the competent health insurance prior to treatment initiation. Clinical trials often have strict inclusion criteria and are, therefore, not easily accessible to many patients. As shown in the SAFIR01 trial, only a small number of patients benefit from personalized therapies mostly due to drug access problems. This problem could be solved by establishing a portfolio of early phase clinical basket trials or by early-access-programs [38]. Recent studies suggest that the implementation of a MTB improves access to targeted therapy [39]. As seen in our clinic, the early-access-program that we started in November 2019 enabled many patients with a PIK3CA mutation to derive benefit from the targeted drug alpelisib soon after its FDA approval in spring 2019 [40]. Third, another major limitation is the testing of tumors from patients with late stage disease, which limits treatment options and hinders patients from receiving the recommended therapy or from enrolling in a clinical trial. As patients in an advanced cancer situation are often in an unstable health condition, obtaining biopsy material with a good quality of tissue is quite difficult. Our study had 14 (14.7%) technically unsuccessful molecular diagnostics. Moreover, the time between enrolling patients in the study, processing tumor samples, followed by the molecular diagnostics and the MTB case discussion is still rather lengthy in view of the fact that malignancies in late stages tend to evolve at unprecedented speed, while causing deterioration of the general condition and hindering patients from receiving particular therapies, one of the main reasons for the relative low number of implemented therapies (9 out of 34). In this study, molecular profiling and discussion were completed in a clinically reasonable time frame of approximately 4 weeks, which is comparable to the median turnaround times in other studies. Therefore, it is reasonable to expect that introducing molecular profiling at an earlier time point in a patient’s disease trajectory could improve the quality of molecular diagnostics and allow patients to benefit more from a multidisciplinary tailored MTB-based treatment advice. Fourth, another concern is that the current trend of identifying single variables and matching it with an appropriate targeted therapy may be irrelevant for some patients because of the heterogeneous landscape of their cancer. Disease variability among individual tumors causes patients with tumors of similar histology to respond differently to targeted therapies [41–43]. For example, only 60% of lung cancer patients with the p.L858R mutation in the epidermal growth factor receptor gene (EGFR) respond to gefitinib, although all of them are carriers of the exact same mutation in the target gene, indicating that other, yet unknown genetic aberrations may influence the effect of targeted drugs and that the disease course is still unpredictable to a great extent [44]. Fifth, the common use of medicines outside the approved label is controversial. Off-label drug use may represent a danger for patient safety in some cases, but it is sometimes justified from a clinical point of view. Four out of nine (44%) of the implemented recommended therapies in the study “The informative Patient” included off-label drugs; two of these patients (50%) experienced a clinical benefit with a partial response or stabilization lasting over 4 months, while having progressed under last standard treatment. There were several limitations to our study. First, despite a relatively high number of breast and gynecological cancer, the overall number of included patients remains low. Second, our patient cohort presented had a heterogeneous tumor type, making general conclusions relatively difficult. Third, the number of patients with implemented therapies is limited, due to deterioration of patients’ general condition or no access to the recommended targeted drug, as previously reported in other studies. Nevertheless, we do demonstrate feasibility of and patient benefit from a routine MTB at a large comprehensive cancer center. Conclusion The landscape of molecular alterations in breast and gynecological cancers is heterogeneous. Advances in the quality and availability of molecular diagnostics and the number of targeted therapies increase rapidly, offering patients with advanced cancer a variety of new treatment options. MTBs try to bridge the gap in between molecular alterations and matching drugs in a structured manner. The primary objective of the present monocentric study was to estimate, in a real-world setting, the impact of interdisciplinary MTB case discussions for patients with breast and gynecological malignancies. Altogether, on the basis of individual molecular diagnostics, diagnostic and treatment recommendations were made for 45 patients (47.4% of all). Nine out of 34 patients received the recommended treatment. Four out of 9 patients responded with a PFSr > 1.3. Therefore, our results support the approach of matching specific drugs (in- and off-label) to particular genetic aberrations and demonstrate its relevance in breast and gynecological cancers for a small, but clinically relevant group of patients. By providing a multidisciplinary tailored-based treatment advice based on genetic tests, it is now possible for more patients with breast and gynecological malignancies to gain maximum clinical benefit and improve survival of patients with either advanced stage cancer or a rare tumor entity by applying personalized medicine. The MTB strategy, however, needs to be standardized and optimized in order to eliminate major logistical problems such as limited access to targeted agents (often off-label) and clinical trials, as well as patient referral at stage disease that are too late for a beneficial therapeutic intervention. Appendix See Table Table 5 Data supplement # Mutation Tumor entity Treatment recommended in MTB Followed treatment / Line of therapy PFS (months) after start of treatment 1 FGFR1, androgen receptor and CCND1 amplifications Breast 1. CDK4/6 Inhibitor 2. Everolimus 3. androgen receptor blocker 2 CCND1 amplification Breast 1. CDK4/6 Inhibitor 2. Palbociclib + Fulvestrant 3. Everolimus Palbociclib 21 3 ERBB2 mutation Breast Afatinib / Neratinib 4 PTEN deletion; MET mutation Breast 1. NCT03337724 trial 2. Exemestan + Everolimus 5 PIK3CA mutation Breast Everolimus 6 MET Exon 14 mutation Breast Crizotinib 7 MYC, FGFR1 and CCND1 amplifications Breast Everolimus Everolimus 13 8 androgen receptor amplification Breast 1. NCT01945775 / NCT02163694 trial 2. Bicalutamide / Tamoxifen 9 PIK3CA mutation Breast 1. SOLAR-1 / IPATunity130 trial 2. Everolimus 10 ERBB2 amplification Breast Lapatinib, Trastuzumab, Emtansine and Pertuzumab 11 ARID1A and PIK3CA mutations, LMB (4,16 muts/MB) Breast Everolimus Everolimus 12 12 ESR1 mutation, CCND1 amplification Breast Fulvestrant + Everolimus 13 TP53 and NOTCH1 mutations Breast Cyclophosphamid 14 TPM3(7)—NTRK1(10) gene fusion Breast NCT02568267 trial 15 MET Exon 2 mutation Breast Cabozantinib 16 KRAS and 2 PIK3CA mutations Breast lipos. Doxorubicin / Bevacizumab + Temsirolimus/ Everolimus 17 androgen receptor mutation, PIK3CA mutation Breast Everolimus 18 FGFR1, CCND1, EGFR, PIK3CA and PDGFRA amplifications Breast Pazopanib 19 ESR1 and PIK3CA mutations Breast 1. NCT03056755 trial 2. Everolimus 20 p16 high expression and MYC mutation Breast Checkpoint inhibitor Pembrolizumab 59 21 androgen receptor amplification Breast Androgen receptor blocker 22 AKT mutation Breast 1. AKT inhibitors 2. IPATunity130 trial 3. Everolimus 23 SLX4 and TP53 mutations; amplifications: FGFR1, CCND1, FGF19, FGFR3 Breast Pazopanib Pazopanib 12 24 ESR1 mutation Breast Fulvestrant + CDK4/6 Inhibitoren 25 CCND1 and FGFR1 amplifications Breast 1. Everolimus + antihormonal therapy; 2. Dovitinib 26 PIK3CA and ERBB2 mutations, high expression ERBB2 Breast 1. Pertuzumab/ Trastuzumab (+ Everolimus) 2. Neratinib Lapatinib 18 27 FGFR1 amplification Breast antihormonal therapy + Everolimus + Trastuzumab Exemestan + Everolimus + Trastuzumab 4 28 CCND1 amplification Breast 1. Exemestan + Everolimus; 2. NCT-MASTER / TOP-ART trial 29 CCND1 and FGFR1 amplifications Breast 1. Everolimus + Exemestan 2. NCT03517956 trial Everolimus + Exemestan 14 30 KRAS and ERBB2 mutations Ovary NCT02703571 trial 31 ERBB2, MYC, PIK3CA amplifications Ovary Everolimus + Letrozol 32 PIK3CA alteration Cervix Temsirolimus Temsirolimus 32 33 PIK3CA and KRAS mutations, MET gene fusion Cervix 1. Crizotinib 2. Everolimus 34 KRAS, SMAD4 and PTEN mutations Endometrium Everolimus 35 HTB (27 muts/MB) Other 1. Checkpoint inhibitor 2. NCT Master trial 36 EML4-ALK gene fusion Other ALK inhibitor 5. Author contributions ES: Manuscript writing, Data management. BW: Project development, Data collection and management, Manuscript editing. AJ: Data collection, Manuscript editing. JK: Data collection, Manuscript editing. TK: Data collection, Manuscript editing. DM: Data collection, Manuscript editing. MR: Data collection, Manuscript editing. SO: Data collection, Manuscript editing. VH: Project development, Manuscript editing. KHM: Data collection, Manuscript editing. PAG: Data collection, Manuscript editing. AB: Data collection, Manuscript editing. FT: Data collection, Manuscript editing. SM: Manuscript editing, Manuscript editing. NH: Manuscript editing, Manuscript editing. RW: Project development, Data collection and management, Manuscript editing. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest statement CBW received personal and speakers’ fees, reimbursement for travel and accommodation and honoraria for participance in advisory boards from Bayer, Celgene, Ipsen, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta and Taiho and grant support by Roche. AJ received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from Amgen, AstraZeneca, Biocartis, Bristo-Myers Squibb (BMS), Boehringer Ingelheim, Chinese Society for Pathology, German Society for Pathology, European Association for Cancer Research (EACR), International Association for Pathology (IAP), Merck-Serono, Merck-Sharp Dohme (MSD), Quality Initiative in Pathology (QuIP), Roche Pharma, Takeda; JK received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Novartis, Quality Initiative in Pathology (QuIP), Roche Pharma. TK received honoraria and reimbursement for travel and accommodation for participance in advisory boards from Amgen, AstraZeneca, Merck KGaA, MSD, Novartis, Pfizer, Roche; and from speaker's bureau from Merck and Astra Zeneca; from Merck and Roche research funding as well. KHM received honoraria from Celgene, Pfizer, Astellas, Daiichi Sankyo and Otsuka Pharma. AB received honoraria and reimbursement for travel and accommodation for participance in advisory boards from AstraZeneka, Roche and Tesaro. FT received research support, reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Clovis, Medac, PharmaMar, Roche, Tesaro/GSK. SM received research support, advisory board, honoraria and travel expenses from AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Medac, MSD, Novartis, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro. NH received honoraria for lectures and/or consulting from Agendia, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. RW received honoraria for lectures and/or consulting from Agendia, Amgen, Aristo, Astra Zeneca, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. Ethical approval The study received approval of the local ethics committee (study number: 284–10) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to participate and publication: Informed consent was obtained from all individual participants included in the study. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	EVEROLIMUS, EXEMESTANE, TRASTUZUMAB	DrugsGivenReaction	CC BY	33277683	19,645,107	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.	NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU. Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months. In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. 284-10 (03.05.2018). Introduction In women, metastatic breast cancer and gynecological malignancies are among the most frequent causes of cancer death. In 2018, there were an estimated 2,088,849 new cases of breast cancer and 626,679 deaths, 569,847 new cases of cervical cancer and 311 365 deaths, and 295,414 new cases of ovarian cancer and 184,799 deaths worldwide. [1] Despite rising overall incidence, mortality rate has steadily decreased owing to early detection and improvements in the therapeutic management of these patients. However, although the development of new drugs, vaccines, and systematic screening programs has improved patients’ outcomes, effective measures to successfully treat metastatic cancer are still missing. With the advent of molecular diagnostics, cancer treatment entered a new era. New techniques of sequencing DNA such as comprehensive genomic profiling (CGP) and hotspot next generation sequencing (NGS) provide tools for deciphering complete genes and later entire genomes at unprecedented speed [2]. These new approaches led to the development of a novel cancer treatment movement, known as precision medicine. By selecting the most effective treatment based on the molecular characteristics of tumor tissues or some other biologic parameters of the malignant disease, precision medicine aims to offer personalized treatment concepts to cancer patients with limited standard of care options. Molecular therapeutic agents (MTA) targeting individual actionable molecular alterations have been successfully developed in the past few years, showing the positive impact of using molecular-based therapy on the cancer patients’ outcome [3–6]. These include the use of growth factor receptor 2 antibody trastuzumab in breast cancer, a tyrosine kinase inhibitor imatinib in myelogenous leukemia associated with the BCR-ABL fusion gene and EGFR tyrosine kinase inhibitors in lung carcinomas [7, 8]. Breast and gynecological cancers constitute a heterogeneous group of malignant diseases associated with multiple genetic alterations [9–11]. In the past few years, a growing number of molecular markers in breast cancer, for example, have been investigated and some of them are now well-established as reliable predictors of prognosis and response to tumor therapy (Fig. 1a). Moreover, many different targeted therapies have been approved for use in breast cancer treatment (Fig. 1b). The recent approval of the PIK3CA specific inhibitor alpelisib has been the most recent example of targeted agents moving into routine care. [12] Treatment with alpelisib was shown to prolong PFS by more than 6 months compared to the control arm. [13]Fig. 1 Predictive factors (a) and treatment-relevant genetic alterations (b) in metastatic breast cancer, German Gynecological Oncology Group. In 2018, AGO was the first international guideline-commission to make recommendations regarding precision medicine in breast cancer. (http://www.ago-online.de) [14] In gynecologic malignancies, MTAs have also been successfully implemented into clinical care. For example, early data from a clinical phase II trial focusing on BRCA-mutated ovarian cancer showed that olaparib as maintenance treatment significantly improved progression-free survival (PFS) in relapsed platinum-sensitive ovarian cancer [15]. In 2018, these data could be transferred to the first line setting when treatment effects of the SOLO1 trial were presented [16]. Due to an impressive PFS improvement and a 70% lower risk of disease progression or death with olaparib compared to placebo, this effect led to the incorporation of PARP inhibitors into the primary treatment of ovarian cancer in 2019 [17]. However, when it comes to other gynecologic malignancies such as endometrial cancer, the development of MTA is delayed in comparison to other malignancies. By detecting potential actionable pathways using molecular diagnostics, it is also possible to assess and treat various cancer types. For example, the ERBB2/PIK3/AKT/mTOR pathway is known for its relevance in breast cancer, but recently a relevant actionable mutation from the same pathway, PIK3R1W624R was also identified in ovarian cancer [18]. Another study suggested that some subtypes of cervical cancers may also benefit from existing ERBB2/PIK3/AKT/mTOR targeted agents [19]. With the rising number of MTAs and considering the heterogeneous molecular profiles of breast cancer and gynecological malignancies, it is reasonable to expect that patients with these malignancies could potentially benefit from implementation of precision oncology based on comprehensive genomic profiling (CGP) into clinical care. Promising early data for such malignancies has been presented in multiple trials. In breast cancer, many reports of such driver alterations have emerged in the past few years, suggesting that patients could profit from precision medicine and targeted therapies [20]. For example, in the SAFIR01 multicenter prospective trial, data of precision medicine benefitting breast cancer patients were presented. 9 out of 43 patients (21%) responded to the recommended targeted therapy with a stable disease lasting over 16 weeks [21]. In ovarian cancer, multiplatform molecular profiling, conducted in a commercially available profiling center, led to a significantly longer post-profiling survival in patients, who were treated with profile-guided targeted agents, in comparison to the control group [22]. With the technical advances in molecular diagnostics and the continuous approval of many targeted therapies, the growing field of precision medicine is constantly expanding and requires optimization. Considering the complexity of precision medicine in oncology, it was reasonable to create a molecular tumor board (MTB) to leverage the knowledge of the many different disciplines involved in oncological treatment and to provide optimal treatment recommendations. In this manuscript, first experiences of the Comprehensive Cancer Center (CCC) LMU Munich Molecular Tumor Board are presented. The aim of this project was to retrospectively measure the impact of MTB discussions and recommendations made by a multidisciplinary tumor board on outcome of patients with breast and gynecological cancers progressing under standard treatment. Detailed information including data on patient characteristics, diagnostic and treatment recommendations, implementation of the recommendations, and outcome of treated patients with breast and gynecological cancers (ovarian, endometrial, cervix, and other type of cancer) are presented. Materials and methods All patients reported here were discussed in the local MTB, which reviewed clinical cases and the respective tumor profiles with the associated actionable alterations. The final result of each MTB case discussion was a report, focused on NGS data and diagnostic and potential diagnostic, and therapeutic alternatives. Thereby, the MTB presented itself as a multidisciplinary team (MDT), which comprised clinical oncologists, pathologists, molecular pathologists, genetic counselors, bioinformaticians, and scientists with expertise in genetic and tumor profiling in diverse cancers. MTB-meetings were held every 2 weeks with the purpose of interpretation and/or translation of the molecular diagnostics’ results into diagnostic and/or treatment recommendations. All patients’ cases were first presented at organ-specific gynecology tumor boards by a team of experienced gyneco-oncologists, who reviewed all the clinical course of every individual patient and discussed if patients were eligible for a MTB discussion. Apart from recent tumor material, recent radiology images and other diagnostic tests were also required for the interdisciplinary setting of the MTB. All treatment recommendations were supported by levels of evidence by using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). The process from enrolling the patient into the study till receiving a recommendation by the MTB is shown in Fig. 2.Fig. 2 MTB, from suggestion to conclusion Patients and patient informed consent All patients discussed (n = 95) were included in the prospective single-center case study, “The informative Patient”, launched in March 2017 at the LMU University Hospital, Munich as a Munich-site part of the DKTK (German Cancer Consortium) program. All enrolled patients suffered from metastatic breast or gynecological cancer which had progressed after at least one line of prior standard treatment and who had no longer access to curative treatment. Prior to inclusion, all participants signed an informed consent that they were informed about potential and limitations that molecular diagnostics could offer for treatment selection and for analysis of their data, further discussion of their case by a multidisciplinary MTB, as well as for collecting follow-up data on the course of disease for research purpose (including requesting patient data from other physicians and institutions). The intention-to-treat (ITT) population consisted of 100 patients. Eventually, five patients were excluded, because of death prior to a treatment recommendation or withdrawal of consent. The data here are based on the results of an ITT population of 95 patients. Molecular pathology Molecular analyses were performed at the Institute of Pathology of the LMU. Appropriate tissue regions were selected histo-morphologically from formalin-fixed paraffin embedded (FFPE)- or fresh frozen tissue. Moreover, liquid biopsies (blood, liquor) were included. In only four patients, analysis had to be repeated due to material constraints. Targeted NGS was performed with the Oncomine Comprehensive Cancer v.3 Panels (Agilent) thereby screening for changes in 161 genes on DNA (SNV, MNV, small ins, del, indels, CNV) and RNA (gene fusions) level. DNA and RNA were isolated using Qiagen's GeneRead DNA FFPE- or RNeasy FFPE-kits, respectively. Nucleic acids (NA; DNA, and RNA) from liquid biopsies were prepared by utilization of the QIAamp Circulating Nucleic Acid Kit. Subsequently, library preparation as first step of NGS was generated by employing Ampliseq Library Plus-, Ampliseq cDNA synthesis-, Ampliseq CD index, Ampliseq Equalizer- together with Ampliseq Comprehensive v3-kits (all Illumina) or DNA- and RNA-Oncomine Comprehensive Panels v3 and Ion AmpliSeq Library-, IonXpress Barcode Adapter-, Ion Library Equalizer-kits together with Ion Chip kits (mostly 550) (all Thermo Fisher), following for each step the respective user manuals. Libraries were run on an Ion Torrent GeneStudio S5 Primer (Thermo Fisher) or Illumina 500 Next Seq (Illumina) NGS machine. Analysis of results was performed with either the Ion-Reporter System (Thermo Fisher) followed by further variant and quality interpretation with a self-made excel tool or annotating VCF-files using wAnnovar (http://wannovar.wglab.org/) [23] together with the self-made python-script PathoMine filtering for clinically relevant mutations. Mutations were judged as relevant on the basis of the key 'interpretation' given in ClinVar [24]. Alterations were confirmed with the Integrated Genomics Viewer (IGV, Broad Institute). The resulting molecular pathological dataset together with data from immunohistochemistry, fluorescence in situ hybridization (FISH), and histo-morphology became part of a comprehensive pathological report which was sent out to the MTB. Data assessment For this analysis, electronic medical records were reviewed for patient characteristics and follow-up. If needed, medical oncologists, gynecologists, and general practitioners were contacted in order to collect follow-up data on treatment course and patient status. Patient characteristics were summarized using descriptive statistics. Follow-up of clinical outcomes was performed to track tumor response to recommended therapies and analyzed by measuring progression-free survival (PFS) of patients, who received the recommended treatment. PFS was calculated from the first day of treatment with the recommended in- or off-label targeted drug until the date of disease progression or death, whichever occurred first, analogous to the Johns Hopkins MTB study and to the Von Hoff et al. study [25]. In order to evaluate the benefit of the treatment recommendation, we then calculated the PFS ratio (PFSr) by comparing the PFS of the recommended treatment and the PFS of the previous therapy of the patients. Cut-off date for data analysis was August 1st, 2019. Results Patient characteristics From March 2017 through March 2019, a total of 95 cases were submitted to the MTB. All patients (n = 95) were females, had an underlying malignant condition, suffered from metastatic disease, and had experienced disease progression under standard treatment. Patients with implemented therapy recommendations had received a median of five (range 2–6) prior therapies for metastatic cancer. The median age at time of the initial MTB presentation was 52 years (range 19–82 years). As shown in Fig. 3, the most frequent tumor type was breast cancer (n = 64, 68%), followed by ovarian cancer (n = 19, 20%). The majority of patients with breast cancer had triple-negative (ER, PR and HER2 negative; n = 30; 46.9%), followed by estrogen receptor (ER) -positive and/or progesterone receptor (PR) -positive, human epidermal growth factor receptor 2 (HER2) -negative (luminal-like) (n = 28; 43.8%), or HER2 positive, ER-negative, PR-negative disease (n = 5; 7.8%) at the time of the MTB case discussion; one patient (1.6%) had triple-positive disease (ER positive and/or PR positive, HER2 positive).Fig. 3 Distribution of the cases discussed at the MTB meeting by tumor entity (n = 95) Characteristics of patients with a molecular profile are reported in Table 1.Table 1 Patient characteristics Covariables Median age at diagnosis 47 years (range 12–80) Age at diagnosis < 30 5 (5.3%) 30–39 27 (28.4%) 40–49 21 (22.1%) 50–59 30 (31.6%) 60–69 8 (8.4%) ≥ 70 4 (4.2%) Median age at MTB case presentation 52 years (range 19–82) Age at MTB case presentation < 30 2 (2.1%) 30–39 19 (20.0%) 40–49 20 (21.1%) 50–59 28 (29.5%) 60–69 18 (18.9%) ≥ 70 8 (8.4%) Molecular profiling Molecular tests using NGS were performed for all 95 patients. Out of the set of mutations from the molecular pathological NGS-analysis, actionable mutations were defined as those matching or informing the use of available targeted agents. Four patients had tumor sequencing performed twice during the course of disease. 81 (85.3%) patients had suitable tissues for multimodal molecular profiling (NGS). All in all, 103 molecular alterations were identified in 55 cases (57.9%). The median number of alterations observed in each sample was one (range 0–6). Out of the 55 patients, 41 (43.2%) had an actionable mutation, which the board reviewed as a potentially targetable. No genomic alterations in the 161 investigated genes were found in 40 (42.1%) analyses, in 14 (14.7%) of which the molecular diagnostics test was technically not successful because of poor DNA quality or insufficient material quality. Although five (5.3%) patients had an actionable mutation, they did not receive a therapy recommendation because of co-morbidities, not meeting trial inclusion criteria, or other requirements for receiving a specific targeted therapy. We discovered mutations in over 30 different genes. Among the patients tested, the most common alterations were as follows: PIK3CA mutation (13/95; 13.7%); ERBB2 mutation (10/95; 10.5%); KRAS mutation (9/95; 9.5%), and CCND1 mutation (9/95; 9.5%). Incidences of genomic alterations by gene and the distribution of molecular alterations by tumor type are shown in Fig. 4.Fig. 4 Frequency of genomic alterations for the different tumor entities (n = 95) Recommendations Among the 55 (57.9%) patients with at least one molecular alteration identified, 41 patients (43.2%) had an actionable alteration, whereas 14 (14.7%) had only non-actionable variants. Eventually, this resulted in 15 diagnostic and 49 treatment recommendations for 45 patients (47.4%). Multiple recommendations were adjusted for 20 (21.1%) patients (multiple recommendation principle). Six patients received a conditional recommendation, which required specific further diagnostics, two of which resulted in a treatment recommendation. Diagnostic recommendations Out of 15 diagnostic recommendations, 10 were pursued. In seven (7.4%) cases, extended genetic analyses were recommended and eventually six (6.3%) of them were performed. Re-biopsies were recommended in 14 cases, when the initial diagnostic tests were technically not successful, which we did not include in the evaluation of the final results. Therapeutic recommendations As shown in Fig. 5, 36 (37.9%) patients were given a therapy recommendation, 14 (14.7%) of whom received more than one treatment suggestion, as their tumor molecular profile revealed more than one actionable mutation. Two (2.1%) patients were excluded from the evaluation of the clinical outcome, as they received the recommended therapy in the period between NGS analysis and MTB treatment recommendation.Fig. 5 Treatment or diagnostic recommendations. Note, all numbers do not add up because some patients are counted in more than one category (e.g., had an actionable alteration for a treatment recommendation and also for diagnostic recommendation or received more than one treatment/ diagnostic recommendation). a Diagram representing the outcome of the molecular diagnostic testing (n = 95). b Breast cancer patients. c Gynecological cancer patients Overall, 9 of 34 therapeutic recommendations were pursued. Of note, in the present cohort, no patient pursued the recommended enrollment in a clinical trial. In-label therapy recommendations were implemented in five cases, whereas off-label recommendations were implemented in four patients. The most common reasons for non-administration of MTB-recommended therapy were deterioration of patients’ physical health condition, early death, no access to the recommended drug therapy, declined reimbursement applications by payer, or patient decision (see Table 2).Table 2 Recommendations (Note, some patients received more than one diagnostic and/or treatment recommendation.) BC GC Patients with min. 1 recommendation No No Diagnostic 8 7 Therapeutic 27 7 No treatment recommendation 30 20 Conditional recommendation 3 3 Referral to organ board 1 Diagnostic recommendations Extended genetic analysis 3 4 PD-L1 Test 2 HR-Status 1 1 Other 5 3 Patients with diagnostic recommendations (n = 15) Implemented 6 4 Non-implemented 2 3 Treatment recommendations Targeted therapy 32 5 Trial inclusion 8 2 Checkpoint inhibition 1 1 Patients with treatment recommendations (n = 36) Implemented 7 1 Non-implemented 22 6 Clinical outcome All patients were included in the registry after multiple standard of care treatments. Out of nine (9.5%) patients following therapy recommendation, 4 (4.2%) showed a state of partial remission or stabilization lasting more than 16 weeks, including two of them receiving off-label therapy recommendation. Comparing PFS of the recommended therapy with the PFS of the previously received systemic treatment, we estimated that four of nine responders receiving MTB-recommended therapies displayed a progression-free survival (PFS) ratio (PFS2/PFS1; PFSr) > 1.3, showing the relevance of the suggested therapies. Two patients responded with an ongoing PFSr. Figure 6 details the actual comparison of PFS on implemented recommended treatment versus PFS on the patient’s last prior treatment.Fig. 6 Comparison of PFS of previous line of therapy (PFS1) and implemented therapy recommendation (PFS2). PFS the period of time between the start of treatment till disease progression/ death More information about the outcome of responding patients is shown in Table 3.Table 3 PFS ratio (PFSr) = ratio of patients’ PFS on the implemented recommended therapy (PFS2) (in this case the recommended in- or off-label targeted drug) to their PFS on the most recent previous line of therapy (standard of care) (PFS1) # Tumor entity Treatment Label PFS2 (weeks) PFS1 (weeks) PFSr 1 Breast Everolimus In 14 81 0.17 2 Breast Everolimus In 12 55 0.22 3 Breast Exemestan + Everolimus + Trastuzumab Off 4 8 0.50 4 Breast Everolimus In 13 13 1.00 5 Breast Pazopanib Off 12 6 2.00 6 Breast Lapatinib In 18 3 6.00 7 Breast Palbociclib In 21 13 1.62 8 Breast Pembrolizumab Off 59 5 11.80 9 Cervix Temsirolimus Off 32 38 0.84 PFSr PFS2/PFS1 See Appendix for details of identified actionable mutations and corresponded treatment recommendations made by the MTB. Discussion We evaluated the clinical consequences of actionable genetic alterations (by NGS) in 95 patients with metastatic breast cancer and gynecological malignancies, part of a pilot monocentric patient registry with the purpose of generating real-world data. Forty-one patients (43.2%) had at least one actionable molecular aberration. The total number of patients with a drug-targetable alteration was 34 (35.7%). Overall, 9 of 34 patients (9.5% of all) received the recommended drug treatment. In a small, but significant group of patients, four out of nine with implemented therapy recommendations (44.4%) experienced a clinical benefit (PFSr > 1.3) lasting over 16 months, a result similar to the one shown by Jameson et al. in cases of patients with metastatic breast cancer, who received personalized therapy recommendations based on multi-omic molecular profiling [26, 27]. Precision medicine offers not only personalized treatment concepts for patients, but also helps us optimize diagnostic and treatment options by identifying biomarkers that are linked to response and resistance to immunotherapy. For instance, in the past few years, the problem of resistance to endocrine therapy has been a point of research. Recently, the key role of the acquisition of ligand-independent ESR1 mutation in breast cancer as a common mechanism of resistance to hormonal therapy was discovered [28]. So far, the precision medicine movement is controversial and has sparked multiple debates. On the one hand, the SHIVA trial (2015), one of the first randomized investigation of precision therapy, was negative for its primary endpoint (progression-free survival [PFS]), as no statistically significant difference in PFS between patients receiving molecularly targeted agents and the control arm was demonstrated [29]. On the other hand, studies recruiting large number of patients, such as MOSCATO 01 (2017) and ProfiLER (2017), suggested that high-throughput genomic analyses (i.e. next-generation sequencing, comprehensive genomic profiling) improve clinical outcome in patients with advanced cancers. However, this approach has only been proven to be beneficial to a small subset of patients so far [30, 31]. As shown in Table 4, studies focusing on precision medicine show different, contradictory results. While in some studies more than 20% of the enrolled patients received the recommended according to molecular profiling treatment, in others the number of patients treated remains very low. These results suggest the need for large data collections in order to improve selection criteria and identify markers that discriminate patients that might benefit most from precision medicine.Table 4 Overview of studies focusing on molecular profiling Author/Study Tumor entity Enrolled patients (n ) MP patients Actionable alterations Implemented therapies—n (% of enrolled) Results Le Tourneau et al. (SHIVA) [29] Solid tumors 741 496 (67%) 293 (40%) 96 (13%) No significant difference in PFS (PFS: 2.3 vs 2.0 p = .41), hazard ratio for death or disease progression, 0.88 (95% CI 0.65–1.19) Stockley et al. (IMPACT/COMPACT) [45] Solid tumors 1893 1640 (87%) 187 (10%) 84 (5%) ORR: 19% in genotype-matched group vs 9% in unmatched group, p = 0.61 Massard et al. (MOSCATO-01) [30] Solid tumors 1035 843 (81%) 411 (40%) 199 (24%) ORR: 11%, SD 52%, PFSr > 1.3: 63/193 (33% of all treated patients or 7% of all enrolled patients) Trédan et al. (PROFILER) [31] Solid tumors 2579 1980 (77%) 1032 (40%) 163 (6%) ORR: 0.9% of all patients Rodon et al. (WINTHER) [46] Solid tumors 303 303 (100%) 25 (89%) 107 (35%) PFSr > 1.5: 22% of the patients with MP-based treatment Hoefflin et al. [47] Solid tumors 198 n.a 104 (53%) 33 (17%) PR: 11/33 (33.3% of all treated patients or 5.5% of all enrolled patients) SD: 8/33 (24.2% of all treated patients or 4% of all enrolled patients) André et al. (SAFIR01/UNICANCER) [21] Breast cancer 423 299 (71%) 195 (46%) 55 (13%) ORR:4 patients had a partial response and 9 had SD > 16 weeks (3% of all patients) Parker et al. [27] Breast cancer 43 43 (100%) 40 (93%) 17 (40%) 7 patients (41% of all treated patients or 16% of all enrolled patients) achieved SD or PR MP molecular profiled, PFS progression-free survival, ORR overall response rate, SD stable disease, PR disease progression, n.a. not available Although molecular targeted agents themselves are more precise than standard cytotoxic agents, clinical evidence for a significant better outcome associated with MTAs is still missing, as the access to targeted therapies remains limited, making collecting data regarding their efficacy difficult. In order to achieve their implementation in clinical care, a re-assessment of the standards of evidence sufficient to prove the benefit of precision cancer therapies is needed [32]. New evidence suggests that appropriately conducted real-world data studies have the potential to support regulatory decisions in the absence of RCT data [33]. Based on initial results of the CCC LMU Munich, patients of various tumor entities benefit from extended molecular diagnostics and their implementation in clinical care [34]. Recently, many studies have described the positive effect of MTB case discussions for particular groups of patients with advanced solid cancers. However, there is not enough evidence for the utility of MTB decisions for patients with breast and gynecological malignancies. The world of precision medicine is constantly evolving, and new targeted therapies are being developed and approved, enabling more and more patients (with up to this point of time not actionable mutation) to receive targeted therapies. For example, in spring 2019, the Food and Drug Administration of the USA (FDA) approved the PIK3CA inhibitor alpelisib in combination with endocrine therapy for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. The availability of this drug after start of the Managed Access Program in our clinic could have resulted in five further therapy recommendations in our MTB cohort, showing the need of identifying such alterations in cancer patients. The rising number of active targetable mutations affects the complexity of the results, making their interpretation a challenge for many oncologists. In 2014, Gray et al. conducted a study, which evaluated cancer physicians’ ability of using multiplex tumor genomic testing and showed that many physicians lack confidence in interpreting complex genomic test results as well as in incorporating them into practice [35]. Thus, we see great potential in establishing the combination of molecular diagnostic tests and a subsequent case discussion by a multidisciplinary molecular board team not only as a routine for cancer patients but also as a training platform and a knowledge-expanding approach for oncologists to help guide their decisions. However, precision oncology faces some challenges, which delay its widespread translation into clinical practice. Critics of the incorporation of NGS and similar methods into clinical practice express following concerns: First, the significant cost of molecular diagnostics and targeted drugs is still a great disadvantage. While prices of next-generation sequencing technologies are dropping from about $3 billion in the year 2000 and to $5000 today, the selection of molecular targeted agents is still enormously expensive [36]. As the price of precision medicine is still rather high for most patients, it is now crucial to also evaluate its cost-effectiveness in order to support its translation into clinical practice, for example in the setting of clinical trials and research programs [37]. Second, logistical problems causing limited access to targeted drugs and clinical trials for biomarker-positive patients represent another major problem. This is mainly due to the absence of reimbursement for drugs beyond their labelled indication. As a consequence, in order to receive the required, often off-label drug, patients need to be enrolled within active clinical trials or are required to cover the costs themselves or to file an application for reimbursement by the competent health insurance prior to treatment initiation. Clinical trials often have strict inclusion criteria and are, therefore, not easily accessible to many patients. As shown in the SAFIR01 trial, only a small number of patients benefit from personalized therapies mostly due to drug access problems. This problem could be solved by establishing a portfolio of early phase clinical basket trials or by early-access-programs [38]. Recent studies suggest that the implementation of a MTB improves access to targeted therapy [39]. As seen in our clinic, the early-access-program that we started in November 2019 enabled many patients with a PIK3CA mutation to derive benefit from the targeted drug alpelisib soon after its FDA approval in spring 2019 [40]. Third, another major limitation is the testing of tumors from patients with late stage disease, which limits treatment options and hinders patients from receiving the recommended therapy or from enrolling in a clinical trial. As patients in an advanced cancer situation are often in an unstable health condition, obtaining biopsy material with a good quality of tissue is quite difficult. Our study had 14 (14.7%) technically unsuccessful molecular diagnostics. Moreover, the time between enrolling patients in the study, processing tumor samples, followed by the molecular diagnostics and the MTB case discussion is still rather lengthy in view of the fact that malignancies in late stages tend to evolve at unprecedented speed, while causing deterioration of the general condition and hindering patients from receiving particular therapies, one of the main reasons for the relative low number of implemented therapies (9 out of 34). In this study, molecular profiling and discussion were completed in a clinically reasonable time frame of approximately 4 weeks, which is comparable to the median turnaround times in other studies. Therefore, it is reasonable to expect that introducing molecular profiling at an earlier time point in a patient’s disease trajectory could improve the quality of molecular diagnostics and allow patients to benefit more from a multidisciplinary tailored MTB-based treatment advice. Fourth, another concern is that the current trend of identifying single variables and matching it with an appropriate targeted therapy may be irrelevant for some patients because of the heterogeneous landscape of their cancer. Disease variability among individual tumors causes patients with tumors of similar histology to respond differently to targeted therapies [41–43]. For example, only 60% of lung cancer patients with the p.L858R mutation in the epidermal growth factor receptor gene (EGFR) respond to gefitinib, although all of them are carriers of the exact same mutation in the target gene, indicating that other, yet unknown genetic aberrations may influence the effect of targeted drugs and that the disease course is still unpredictable to a great extent [44]. Fifth, the common use of medicines outside the approved label is controversial. Off-label drug use may represent a danger for patient safety in some cases, but it is sometimes justified from a clinical point of view. Four out of nine (44%) of the implemented recommended therapies in the study “The informative Patient” included off-label drugs; two of these patients (50%) experienced a clinical benefit with a partial response or stabilization lasting over 4 months, while having progressed under last standard treatment. There were several limitations to our study. First, despite a relatively high number of breast and gynecological cancer, the overall number of included patients remains low. Second, our patient cohort presented had a heterogeneous tumor type, making general conclusions relatively difficult. Third, the number of patients with implemented therapies is limited, due to deterioration of patients’ general condition or no access to the recommended targeted drug, as previously reported in other studies. Nevertheless, we do demonstrate feasibility of and patient benefit from a routine MTB at a large comprehensive cancer center. Conclusion The landscape of molecular alterations in breast and gynecological cancers is heterogeneous. Advances in the quality and availability of molecular diagnostics and the number of targeted therapies increase rapidly, offering patients with advanced cancer a variety of new treatment options. MTBs try to bridge the gap in between molecular alterations and matching drugs in a structured manner. The primary objective of the present monocentric study was to estimate, in a real-world setting, the impact of interdisciplinary MTB case discussions for patients with breast and gynecological malignancies. Altogether, on the basis of individual molecular diagnostics, diagnostic and treatment recommendations were made for 45 patients (47.4% of all). Nine out of 34 patients received the recommended treatment. Four out of 9 patients responded with a PFSr > 1.3. Therefore, our results support the approach of matching specific drugs (in- and off-label) to particular genetic aberrations and demonstrate its relevance in breast and gynecological cancers for a small, but clinically relevant group of patients. By providing a multidisciplinary tailored-based treatment advice based on genetic tests, it is now possible for more patients with breast and gynecological malignancies to gain maximum clinical benefit and improve survival of patients with either advanced stage cancer or a rare tumor entity by applying personalized medicine. The MTB strategy, however, needs to be standardized and optimized in order to eliminate major logistical problems such as limited access to targeted agents (often off-label) and clinical trials, as well as patient referral at stage disease that are too late for a beneficial therapeutic intervention. Appendix See Table Table 5 Data supplement # Mutation Tumor entity Treatment recommended in MTB Followed treatment / Line of therapy PFS (months) after start of treatment 1 FGFR1, androgen receptor and CCND1 amplifications Breast 1. CDK4/6 Inhibitor 2. Everolimus 3. androgen receptor blocker 2 CCND1 amplification Breast 1. CDK4/6 Inhibitor 2. Palbociclib + Fulvestrant 3. Everolimus Palbociclib 21 3 ERBB2 mutation Breast Afatinib / Neratinib 4 PTEN deletion; MET mutation Breast 1. NCT03337724 trial 2. Exemestan + Everolimus 5 PIK3CA mutation Breast Everolimus 6 MET Exon 14 mutation Breast Crizotinib 7 MYC, FGFR1 and CCND1 amplifications Breast Everolimus Everolimus 13 8 androgen receptor amplification Breast 1. NCT01945775 / NCT02163694 trial 2. Bicalutamide / Tamoxifen 9 PIK3CA mutation Breast 1. SOLAR-1 / IPATunity130 trial 2. Everolimus 10 ERBB2 amplification Breast Lapatinib, Trastuzumab, Emtansine and Pertuzumab 11 ARID1A and PIK3CA mutations, LMB (4,16 muts/MB) Breast Everolimus Everolimus 12 12 ESR1 mutation, CCND1 amplification Breast Fulvestrant + Everolimus 13 TP53 and NOTCH1 mutations Breast Cyclophosphamid 14 TPM3(7)—NTRK1(10) gene fusion Breast NCT02568267 trial 15 MET Exon 2 mutation Breast Cabozantinib 16 KRAS and 2 PIK3CA mutations Breast lipos. Doxorubicin / Bevacizumab + Temsirolimus/ Everolimus 17 androgen receptor mutation, PIK3CA mutation Breast Everolimus 18 FGFR1, CCND1, EGFR, PIK3CA and PDGFRA amplifications Breast Pazopanib 19 ESR1 and PIK3CA mutations Breast 1. NCT03056755 trial 2. Everolimus 20 p16 high expression and MYC mutation Breast Checkpoint inhibitor Pembrolizumab 59 21 androgen receptor amplification Breast Androgen receptor blocker 22 AKT mutation Breast 1. AKT inhibitors 2. IPATunity130 trial 3. Everolimus 23 SLX4 and TP53 mutations; amplifications: FGFR1, CCND1, FGF19, FGFR3 Breast Pazopanib Pazopanib 12 24 ESR1 mutation Breast Fulvestrant + CDK4/6 Inhibitoren 25 CCND1 and FGFR1 amplifications Breast 1. Everolimus + antihormonal therapy; 2. Dovitinib 26 PIK3CA and ERBB2 mutations, high expression ERBB2 Breast 1. Pertuzumab/ Trastuzumab (+ Everolimus) 2. Neratinib Lapatinib 18 27 FGFR1 amplification Breast antihormonal therapy + Everolimus + Trastuzumab Exemestan + Everolimus + Trastuzumab 4 28 CCND1 amplification Breast 1. Exemestan + Everolimus; 2. NCT-MASTER / TOP-ART trial 29 CCND1 and FGFR1 amplifications Breast 1. Everolimus + Exemestan 2. NCT03517956 trial Everolimus + Exemestan 14 30 KRAS and ERBB2 mutations Ovary NCT02703571 trial 31 ERBB2, MYC, PIK3CA amplifications Ovary Everolimus + Letrozol 32 PIK3CA alteration Cervix Temsirolimus Temsirolimus 32 33 PIK3CA and KRAS mutations, MET gene fusion Cervix 1. Crizotinib 2. Everolimus 34 KRAS, SMAD4 and PTEN mutations Endometrium Everolimus 35 HTB (27 muts/MB) Other 1. Checkpoint inhibitor 2. NCT Master trial 36 EML4-ALK gene fusion Other ALK inhibitor 5. Author contributions ES: Manuscript writing, Data management. BW: Project development, Data collection and management, Manuscript editing. AJ: Data collection, Manuscript editing. JK: Data collection, Manuscript editing. TK: Data collection, Manuscript editing. DM: Data collection, Manuscript editing. MR: Data collection, Manuscript editing. SO: Data collection, Manuscript editing. VH: Project development, Manuscript editing. KHM: Data collection, Manuscript editing. PAG: Data collection, Manuscript editing. AB: Data collection, Manuscript editing. FT: Data collection, Manuscript editing. SM: Manuscript editing, Manuscript editing. NH: Manuscript editing, Manuscript editing. RW: Project development, Data collection and management, Manuscript editing. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest statement CBW received personal and speakers’ fees, reimbursement for travel and accommodation and honoraria for participance in advisory boards from Bayer, Celgene, Ipsen, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta and Taiho and grant support by Roche. AJ received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from Amgen, AstraZeneca, Biocartis, Bristo-Myers Squibb (BMS), Boehringer Ingelheim, Chinese Society for Pathology, German Society for Pathology, European Association for Cancer Research (EACR), International Association for Pathology (IAP), Merck-Serono, Merck-Sharp Dohme (MSD), Quality Initiative in Pathology (QuIP), Roche Pharma, Takeda; JK received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Novartis, Quality Initiative in Pathology (QuIP), Roche Pharma. TK received honoraria and reimbursement for travel and accommodation for participance in advisory boards from Amgen, AstraZeneca, Merck KGaA, MSD, Novartis, Pfizer, Roche; and from speaker's bureau from Merck and Astra Zeneca; from Merck and Roche research funding as well. KHM received honoraria from Celgene, Pfizer, Astellas, Daiichi Sankyo and Otsuka Pharma. AB received honoraria and reimbursement for travel and accommodation for participance in advisory boards from AstraZeneka, Roche and Tesaro. FT received research support, reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Clovis, Medac, PharmaMar, Roche, Tesaro/GSK. SM received research support, advisory board, honoraria and travel expenses from AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Medac, MSD, Novartis, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro. NH received honoraria for lectures and/or consulting from Agendia, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. RW received honoraria for lectures and/or consulting from Agendia, Amgen, Aristo, Astra Zeneca, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. Ethical approval The study received approval of the local ethics committee (study number: 284–10) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to participate and publication: Informed consent was obtained from all individual participants included in the study. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	EVEROLIMUS, EXEMESTANE, TRASTUZUMAB	DrugsGivenReaction	CC BY	33277683	19,645,107	2021-05
What was the outcome of reaction 'Breast cancer'?	NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU. Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months. In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. 284-10 (03.05.2018). Introduction In women, metastatic breast cancer and gynecological malignancies are among the most frequent causes of cancer death. In 2018, there were an estimated 2,088,849 new cases of breast cancer and 626,679 deaths, 569,847 new cases of cervical cancer and 311 365 deaths, and 295,414 new cases of ovarian cancer and 184,799 deaths worldwide. [1] Despite rising overall incidence, mortality rate has steadily decreased owing to early detection and improvements in the therapeutic management of these patients. However, although the development of new drugs, vaccines, and systematic screening programs has improved patients’ outcomes, effective measures to successfully treat metastatic cancer are still missing. With the advent of molecular diagnostics, cancer treatment entered a new era. New techniques of sequencing DNA such as comprehensive genomic profiling (CGP) and hotspot next generation sequencing (NGS) provide tools for deciphering complete genes and later entire genomes at unprecedented speed [2]. These new approaches led to the development of a novel cancer treatment movement, known as precision medicine. By selecting the most effective treatment based on the molecular characteristics of tumor tissues or some other biologic parameters of the malignant disease, precision medicine aims to offer personalized treatment concepts to cancer patients with limited standard of care options. Molecular therapeutic agents (MTA) targeting individual actionable molecular alterations have been successfully developed in the past few years, showing the positive impact of using molecular-based therapy on the cancer patients’ outcome [3–6]. These include the use of growth factor receptor 2 antibody trastuzumab in breast cancer, a tyrosine kinase inhibitor imatinib in myelogenous leukemia associated with the BCR-ABL fusion gene and EGFR tyrosine kinase inhibitors in lung carcinomas [7, 8]. Breast and gynecological cancers constitute a heterogeneous group of malignant diseases associated with multiple genetic alterations [9–11]. In the past few years, a growing number of molecular markers in breast cancer, for example, have been investigated and some of them are now well-established as reliable predictors of prognosis and response to tumor therapy (Fig. 1a). Moreover, many different targeted therapies have been approved for use in breast cancer treatment (Fig. 1b). The recent approval of the PIK3CA specific inhibitor alpelisib has been the most recent example of targeted agents moving into routine care. [12] Treatment with alpelisib was shown to prolong PFS by more than 6 months compared to the control arm. [13]Fig. 1 Predictive factors (a) and treatment-relevant genetic alterations (b) in metastatic breast cancer, German Gynecological Oncology Group. In 2018, AGO was the first international guideline-commission to make recommendations regarding precision medicine in breast cancer. (http://www.ago-online.de) [14] In gynecologic malignancies, MTAs have also been successfully implemented into clinical care. For example, early data from a clinical phase II trial focusing on BRCA-mutated ovarian cancer showed that olaparib as maintenance treatment significantly improved progression-free survival (PFS) in relapsed platinum-sensitive ovarian cancer [15]. In 2018, these data could be transferred to the first line setting when treatment effects of the SOLO1 trial were presented [16]. Due to an impressive PFS improvement and a 70% lower risk of disease progression or death with olaparib compared to placebo, this effect led to the incorporation of PARP inhibitors into the primary treatment of ovarian cancer in 2019 [17]. However, when it comes to other gynecologic malignancies such as endometrial cancer, the development of MTA is delayed in comparison to other malignancies. By detecting potential actionable pathways using molecular diagnostics, it is also possible to assess and treat various cancer types. For example, the ERBB2/PIK3/AKT/mTOR pathway is known for its relevance in breast cancer, but recently a relevant actionable mutation from the same pathway, PIK3R1W624R was also identified in ovarian cancer [18]. Another study suggested that some subtypes of cervical cancers may also benefit from existing ERBB2/PIK3/AKT/mTOR targeted agents [19]. With the rising number of MTAs and considering the heterogeneous molecular profiles of breast cancer and gynecological malignancies, it is reasonable to expect that patients with these malignancies could potentially benefit from implementation of precision oncology based on comprehensive genomic profiling (CGP) into clinical care. Promising early data for such malignancies has been presented in multiple trials. In breast cancer, many reports of such driver alterations have emerged in the past few years, suggesting that patients could profit from precision medicine and targeted therapies [20]. For example, in the SAFIR01 multicenter prospective trial, data of precision medicine benefitting breast cancer patients were presented. 9 out of 43 patients (21%) responded to the recommended targeted therapy with a stable disease lasting over 16 weeks [21]. In ovarian cancer, multiplatform molecular profiling, conducted in a commercially available profiling center, led to a significantly longer post-profiling survival in patients, who were treated with profile-guided targeted agents, in comparison to the control group [22]. With the technical advances in molecular diagnostics and the continuous approval of many targeted therapies, the growing field of precision medicine is constantly expanding and requires optimization. Considering the complexity of precision medicine in oncology, it was reasonable to create a molecular tumor board (MTB) to leverage the knowledge of the many different disciplines involved in oncological treatment and to provide optimal treatment recommendations. In this manuscript, first experiences of the Comprehensive Cancer Center (CCC) LMU Munich Molecular Tumor Board are presented. The aim of this project was to retrospectively measure the impact of MTB discussions and recommendations made by a multidisciplinary tumor board on outcome of patients with breast and gynecological cancers progressing under standard treatment. Detailed information including data on patient characteristics, diagnostic and treatment recommendations, implementation of the recommendations, and outcome of treated patients with breast and gynecological cancers (ovarian, endometrial, cervix, and other type of cancer) are presented. Materials and methods All patients reported here were discussed in the local MTB, which reviewed clinical cases and the respective tumor profiles with the associated actionable alterations. The final result of each MTB case discussion was a report, focused on NGS data and diagnostic and potential diagnostic, and therapeutic alternatives. Thereby, the MTB presented itself as a multidisciplinary team (MDT), which comprised clinical oncologists, pathologists, molecular pathologists, genetic counselors, bioinformaticians, and scientists with expertise in genetic and tumor profiling in diverse cancers. MTB-meetings were held every 2 weeks with the purpose of interpretation and/or translation of the molecular diagnostics’ results into diagnostic and/or treatment recommendations. All patients’ cases were first presented at organ-specific gynecology tumor boards by a team of experienced gyneco-oncologists, who reviewed all the clinical course of every individual patient and discussed if patients were eligible for a MTB discussion. Apart from recent tumor material, recent radiology images and other diagnostic tests were also required for the interdisciplinary setting of the MTB. All treatment recommendations were supported by levels of evidence by using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). The process from enrolling the patient into the study till receiving a recommendation by the MTB is shown in Fig. 2.Fig. 2 MTB, from suggestion to conclusion Patients and patient informed consent All patients discussed (n = 95) were included in the prospective single-center case study, “The informative Patient”, launched in March 2017 at the LMU University Hospital, Munich as a Munich-site part of the DKTK (German Cancer Consortium) program. All enrolled patients suffered from metastatic breast or gynecological cancer which had progressed after at least one line of prior standard treatment and who had no longer access to curative treatment. Prior to inclusion, all participants signed an informed consent that they were informed about potential and limitations that molecular diagnostics could offer for treatment selection and for analysis of their data, further discussion of their case by a multidisciplinary MTB, as well as for collecting follow-up data on the course of disease for research purpose (including requesting patient data from other physicians and institutions). The intention-to-treat (ITT) population consisted of 100 patients. Eventually, five patients were excluded, because of death prior to a treatment recommendation or withdrawal of consent. The data here are based on the results of an ITT population of 95 patients. Molecular pathology Molecular analyses were performed at the Institute of Pathology of the LMU. Appropriate tissue regions were selected histo-morphologically from formalin-fixed paraffin embedded (FFPE)- or fresh frozen tissue. Moreover, liquid biopsies (blood, liquor) were included. In only four patients, analysis had to be repeated due to material constraints. Targeted NGS was performed with the Oncomine Comprehensive Cancer v.3 Panels (Agilent) thereby screening for changes in 161 genes on DNA (SNV, MNV, small ins, del, indels, CNV) and RNA (gene fusions) level. DNA and RNA were isolated using Qiagen's GeneRead DNA FFPE- or RNeasy FFPE-kits, respectively. Nucleic acids (NA; DNA, and RNA) from liquid biopsies were prepared by utilization of the QIAamp Circulating Nucleic Acid Kit. Subsequently, library preparation as first step of NGS was generated by employing Ampliseq Library Plus-, Ampliseq cDNA synthesis-, Ampliseq CD index, Ampliseq Equalizer- together with Ampliseq Comprehensive v3-kits (all Illumina) or DNA- and RNA-Oncomine Comprehensive Panels v3 and Ion AmpliSeq Library-, IonXpress Barcode Adapter-, Ion Library Equalizer-kits together with Ion Chip kits (mostly 550) (all Thermo Fisher), following for each step the respective user manuals. Libraries were run on an Ion Torrent GeneStudio S5 Primer (Thermo Fisher) or Illumina 500 Next Seq (Illumina) NGS machine. Analysis of results was performed with either the Ion-Reporter System (Thermo Fisher) followed by further variant and quality interpretation with a self-made excel tool or annotating VCF-files using wAnnovar (http://wannovar.wglab.org/) [23] together with the self-made python-script PathoMine filtering for clinically relevant mutations. Mutations were judged as relevant on the basis of the key 'interpretation' given in ClinVar [24]. Alterations were confirmed with the Integrated Genomics Viewer (IGV, Broad Institute). The resulting molecular pathological dataset together with data from immunohistochemistry, fluorescence in situ hybridization (FISH), and histo-morphology became part of a comprehensive pathological report which was sent out to the MTB. Data assessment For this analysis, electronic medical records were reviewed for patient characteristics and follow-up. If needed, medical oncologists, gynecologists, and general practitioners were contacted in order to collect follow-up data on treatment course and patient status. Patient characteristics were summarized using descriptive statistics. Follow-up of clinical outcomes was performed to track tumor response to recommended therapies and analyzed by measuring progression-free survival (PFS) of patients, who received the recommended treatment. PFS was calculated from the first day of treatment with the recommended in- or off-label targeted drug until the date of disease progression or death, whichever occurred first, analogous to the Johns Hopkins MTB study and to the Von Hoff et al. study [25]. In order to evaluate the benefit of the treatment recommendation, we then calculated the PFS ratio (PFSr) by comparing the PFS of the recommended treatment and the PFS of the previous therapy of the patients. Cut-off date for data analysis was August 1st, 2019. Results Patient characteristics From March 2017 through March 2019, a total of 95 cases were submitted to the MTB. All patients (n = 95) were females, had an underlying malignant condition, suffered from metastatic disease, and had experienced disease progression under standard treatment. Patients with implemented therapy recommendations had received a median of five (range 2–6) prior therapies for metastatic cancer. The median age at time of the initial MTB presentation was 52 years (range 19–82 years). As shown in Fig. 3, the most frequent tumor type was breast cancer (n = 64, 68%), followed by ovarian cancer (n = 19, 20%). The majority of patients with breast cancer had triple-negative (ER, PR and HER2 negative; n = 30; 46.9%), followed by estrogen receptor (ER) -positive and/or progesterone receptor (PR) -positive, human epidermal growth factor receptor 2 (HER2) -negative (luminal-like) (n = 28; 43.8%), or HER2 positive, ER-negative, PR-negative disease (n = 5; 7.8%) at the time of the MTB case discussion; one patient (1.6%) had triple-positive disease (ER positive and/or PR positive, HER2 positive).Fig. 3 Distribution of the cases discussed at the MTB meeting by tumor entity (n = 95) Characteristics of patients with a molecular profile are reported in Table 1.Table 1 Patient characteristics Covariables Median age at diagnosis 47 years (range 12–80) Age at diagnosis < 30 5 (5.3%) 30–39 27 (28.4%) 40–49 21 (22.1%) 50–59 30 (31.6%) 60–69 8 (8.4%) ≥ 70 4 (4.2%) Median age at MTB case presentation 52 years (range 19–82) Age at MTB case presentation < 30 2 (2.1%) 30–39 19 (20.0%) 40–49 20 (21.1%) 50–59 28 (29.5%) 60–69 18 (18.9%) ≥ 70 8 (8.4%) Molecular profiling Molecular tests using NGS were performed for all 95 patients. Out of the set of mutations from the molecular pathological NGS-analysis, actionable mutations were defined as those matching or informing the use of available targeted agents. Four patients had tumor sequencing performed twice during the course of disease. 81 (85.3%) patients had suitable tissues for multimodal molecular profiling (NGS). All in all, 103 molecular alterations were identified in 55 cases (57.9%). The median number of alterations observed in each sample was one (range 0–6). Out of the 55 patients, 41 (43.2%) had an actionable mutation, which the board reviewed as a potentially targetable. No genomic alterations in the 161 investigated genes were found in 40 (42.1%) analyses, in 14 (14.7%) of which the molecular diagnostics test was technically not successful because of poor DNA quality or insufficient material quality. Although five (5.3%) patients had an actionable mutation, they did not receive a therapy recommendation because of co-morbidities, not meeting trial inclusion criteria, or other requirements for receiving a specific targeted therapy. We discovered mutations in over 30 different genes. Among the patients tested, the most common alterations were as follows: PIK3CA mutation (13/95; 13.7%); ERBB2 mutation (10/95; 10.5%); KRAS mutation (9/95; 9.5%), and CCND1 mutation (9/95; 9.5%). Incidences of genomic alterations by gene and the distribution of molecular alterations by tumor type are shown in Fig. 4.Fig. 4 Frequency of genomic alterations for the different tumor entities (n = 95) Recommendations Among the 55 (57.9%) patients with at least one molecular alteration identified, 41 patients (43.2%) had an actionable alteration, whereas 14 (14.7%) had only non-actionable variants. Eventually, this resulted in 15 diagnostic and 49 treatment recommendations for 45 patients (47.4%). Multiple recommendations were adjusted for 20 (21.1%) patients (multiple recommendation principle). Six patients received a conditional recommendation, which required specific further diagnostics, two of which resulted in a treatment recommendation. Diagnostic recommendations Out of 15 diagnostic recommendations, 10 were pursued. In seven (7.4%) cases, extended genetic analyses were recommended and eventually six (6.3%) of them were performed. Re-biopsies were recommended in 14 cases, when the initial diagnostic tests were technically not successful, which we did not include in the evaluation of the final results. Therapeutic recommendations As shown in Fig. 5, 36 (37.9%) patients were given a therapy recommendation, 14 (14.7%) of whom received more than one treatment suggestion, as their tumor molecular profile revealed more than one actionable mutation. Two (2.1%) patients were excluded from the evaluation of the clinical outcome, as they received the recommended therapy in the period between NGS analysis and MTB treatment recommendation.Fig. 5 Treatment or diagnostic recommendations. Note, all numbers do not add up because some patients are counted in more than one category (e.g., had an actionable alteration for a treatment recommendation and also for diagnostic recommendation or received more than one treatment/ diagnostic recommendation). a Diagram representing the outcome of the molecular diagnostic testing (n = 95). b Breast cancer patients. c Gynecological cancer patients Overall, 9 of 34 therapeutic recommendations were pursued. Of note, in the present cohort, no patient pursued the recommended enrollment in a clinical trial. In-label therapy recommendations were implemented in five cases, whereas off-label recommendations were implemented in four patients. The most common reasons for non-administration of MTB-recommended therapy were deterioration of patients’ physical health condition, early death, no access to the recommended drug therapy, declined reimbursement applications by payer, or patient decision (see Table 2).Table 2 Recommendations (Note, some patients received more than one diagnostic and/or treatment recommendation.) BC GC Patients with min. 1 recommendation No No Diagnostic 8 7 Therapeutic 27 7 No treatment recommendation 30 20 Conditional recommendation 3 3 Referral to organ board 1 Diagnostic recommendations Extended genetic analysis 3 4 PD-L1 Test 2 HR-Status 1 1 Other 5 3 Patients with diagnostic recommendations (n = 15) Implemented 6 4 Non-implemented 2 3 Treatment recommendations Targeted therapy 32 5 Trial inclusion 8 2 Checkpoint inhibition 1 1 Patients with treatment recommendations (n = 36) Implemented 7 1 Non-implemented 22 6 Clinical outcome All patients were included in the registry after multiple standard of care treatments. Out of nine (9.5%) patients following therapy recommendation, 4 (4.2%) showed a state of partial remission or stabilization lasting more than 16 weeks, including two of them receiving off-label therapy recommendation. Comparing PFS of the recommended therapy with the PFS of the previously received systemic treatment, we estimated that four of nine responders receiving MTB-recommended therapies displayed a progression-free survival (PFS) ratio (PFS2/PFS1; PFSr) > 1.3, showing the relevance of the suggested therapies. Two patients responded with an ongoing PFSr. Figure 6 details the actual comparison of PFS on implemented recommended treatment versus PFS on the patient’s last prior treatment.Fig. 6 Comparison of PFS of previous line of therapy (PFS1) and implemented therapy recommendation (PFS2). PFS the period of time between the start of treatment till disease progression/ death More information about the outcome of responding patients is shown in Table 3.Table 3 PFS ratio (PFSr) = ratio of patients’ PFS on the implemented recommended therapy (PFS2) (in this case the recommended in- or off-label targeted drug) to their PFS on the most recent previous line of therapy (standard of care) (PFS1) # Tumor entity Treatment Label PFS2 (weeks) PFS1 (weeks) PFSr 1 Breast Everolimus In 14 81 0.17 2 Breast Everolimus In 12 55 0.22 3 Breast Exemestan + Everolimus + Trastuzumab Off 4 8 0.50 4 Breast Everolimus In 13 13 1.00 5 Breast Pazopanib Off 12 6 2.00 6 Breast Lapatinib In 18 3 6.00 7 Breast Palbociclib In 21 13 1.62 8 Breast Pembrolizumab Off 59 5 11.80 9 Cervix Temsirolimus Off 32 38 0.84 PFSr PFS2/PFS1 See Appendix for details of identified actionable mutations and corresponded treatment recommendations made by the MTB. Discussion We evaluated the clinical consequences of actionable genetic alterations (by NGS) in 95 patients with metastatic breast cancer and gynecological malignancies, part of a pilot monocentric patient registry with the purpose of generating real-world data. Forty-one patients (43.2%) had at least one actionable molecular aberration. The total number of patients with a drug-targetable alteration was 34 (35.7%). Overall, 9 of 34 patients (9.5% of all) received the recommended drug treatment. In a small, but significant group of patients, four out of nine with implemented therapy recommendations (44.4%) experienced a clinical benefit (PFSr > 1.3) lasting over 16 months, a result similar to the one shown by Jameson et al. in cases of patients with metastatic breast cancer, who received personalized therapy recommendations based on multi-omic molecular profiling [26, 27]. Precision medicine offers not only personalized treatment concepts for patients, but also helps us optimize diagnostic and treatment options by identifying biomarkers that are linked to response and resistance to immunotherapy. For instance, in the past few years, the problem of resistance to endocrine therapy has been a point of research. Recently, the key role of the acquisition of ligand-independent ESR1 mutation in breast cancer as a common mechanism of resistance to hormonal therapy was discovered [28]. So far, the precision medicine movement is controversial and has sparked multiple debates. On the one hand, the SHIVA trial (2015), one of the first randomized investigation of precision therapy, was negative for its primary endpoint (progression-free survival [PFS]), as no statistically significant difference in PFS between patients receiving molecularly targeted agents and the control arm was demonstrated [29]. On the other hand, studies recruiting large number of patients, such as MOSCATO 01 (2017) and ProfiLER (2017), suggested that high-throughput genomic analyses (i.e. next-generation sequencing, comprehensive genomic profiling) improve clinical outcome in patients with advanced cancers. However, this approach has only been proven to be beneficial to a small subset of patients so far [30, 31]. As shown in Table 4, studies focusing on precision medicine show different, contradictory results. While in some studies more than 20% of the enrolled patients received the recommended according to molecular profiling treatment, in others the number of patients treated remains very low. These results suggest the need for large data collections in order to improve selection criteria and identify markers that discriminate patients that might benefit most from precision medicine.Table 4 Overview of studies focusing on molecular profiling Author/Study Tumor entity Enrolled patients (n ) MP patients Actionable alterations Implemented therapies—n (% of enrolled) Results Le Tourneau et al. (SHIVA) [29] Solid tumors 741 496 (67%) 293 (40%) 96 (13%) No significant difference in PFS (PFS: 2.3 vs 2.0 p = .41), hazard ratio for death or disease progression, 0.88 (95% CI 0.65–1.19) Stockley et al. (IMPACT/COMPACT) [45] Solid tumors 1893 1640 (87%) 187 (10%) 84 (5%) ORR: 19% in genotype-matched group vs 9% in unmatched group, p = 0.61 Massard et al. (MOSCATO-01) [30] Solid tumors 1035 843 (81%) 411 (40%) 199 (24%) ORR: 11%, SD 52%, PFSr > 1.3: 63/193 (33% of all treated patients or 7% of all enrolled patients) Trédan et al. (PROFILER) [31] Solid tumors 2579 1980 (77%) 1032 (40%) 163 (6%) ORR: 0.9% of all patients Rodon et al. (WINTHER) [46] Solid tumors 303 303 (100%) 25 (89%) 107 (35%) PFSr > 1.5: 22% of the patients with MP-based treatment Hoefflin et al. [47] Solid tumors 198 n.a 104 (53%) 33 (17%) PR: 11/33 (33.3% of all treated patients or 5.5% of all enrolled patients) SD: 8/33 (24.2% of all treated patients or 4% of all enrolled patients) André et al. (SAFIR01/UNICANCER) [21] Breast cancer 423 299 (71%) 195 (46%) 55 (13%) ORR:4 patients had a partial response and 9 had SD > 16 weeks (3% of all patients) Parker et al. [27] Breast cancer 43 43 (100%) 40 (93%) 17 (40%) 7 patients (41% of all treated patients or 16% of all enrolled patients) achieved SD or PR MP molecular profiled, PFS progression-free survival, ORR overall response rate, SD stable disease, PR disease progression, n.a. not available Although molecular targeted agents themselves are more precise than standard cytotoxic agents, clinical evidence for a significant better outcome associated with MTAs is still missing, as the access to targeted therapies remains limited, making collecting data regarding their efficacy difficult. In order to achieve their implementation in clinical care, a re-assessment of the standards of evidence sufficient to prove the benefit of precision cancer therapies is needed [32]. New evidence suggests that appropriately conducted real-world data studies have the potential to support regulatory decisions in the absence of RCT data [33]. Based on initial results of the CCC LMU Munich, patients of various tumor entities benefit from extended molecular diagnostics and their implementation in clinical care [34]. Recently, many studies have described the positive effect of MTB case discussions for particular groups of patients with advanced solid cancers. However, there is not enough evidence for the utility of MTB decisions for patients with breast and gynecological malignancies. The world of precision medicine is constantly evolving, and new targeted therapies are being developed and approved, enabling more and more patients (with up to this point of time not actionable mutation) to receive targeted therapies. For example, in spring 2019, the Food and Drug Administration of the USA (FDA) approved the PIK3CA inhibitor alpelisib in combination with endocrine therapy for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. The availability of this drug after start of the Managed Access Program in our clinic could have resulted in five further therapy recommendations in our MTB cohort, showing the need of identifying such alterations in cancer patients. The rising number of active targetable mutations affects the complexity of the results, making their interpretation a challenge for many oncologists. In 2014, Gray et al. conducted a study, which evaluated cancer physicians’ ability of using multiplex tumor genomic testing and showed that many physicians lack confidence in interpreting complex genomic test results as well as in incorporating them into practice [35]. Thus, we see great potential in establishing the combination of molecular diagnostic tests and a subsequent case discussion by a multidisciplinary molecular board team not only as a routine for cancer patients but also as a training platform and a knowledge-expanding approach for oncologists to help guide their decisions. However, precision oncology faces some challenges, which delay its widespread translation into clinical practice. Critics of the incorporation of NGS and similar methods into clinical practice express following concerns: First, the significant cost of molecular diagnostics and targeted drugs is still a great disadvantage. While prices of next-generation sequencing technologies are dropping from about $3 billion in the year 2000 and to $5000 today, the selection of molecular targeted agents is still enormously expensive [36]. As the price of precision medicine is still rather high for most patients, it is now crucial to also evaluate its cost-effectiveness in order to support its translation into clinical practice, for example in the setting of clinical trials and research programs [37]. Second, logistical problems causing limited access to targeted drugs and clinical trials for biomarker-positive patients represent another major problem. This is mainly due to the absence of reimbursement for drugs beyond their labelled indication. As a consequence, in order to receive the required, often off-label drug, patients need to be enrolled within active clinical trials or are required to cover the costs themselves or to file an application for reimbursement by the competent health insurance prior to treatment initiation. Clinical trials often have strict inclusion criteria and are, therefore, not easily accessible to many patients. As shown in the SAFIR01 trial, only a small number of patients benefit from personalized therapies mostly due to drug access problems. This problem could be solved by establishing a portfolio of early phase clinical basket trials or by early-access-programs [38]. Recent studies suggest that the implementation of a MTB improves access to targeted therapy [39]. As seen in our clinic, the early-access-program that we started in November 2019 enabled many patients with a PIK3CA mutation to derive benefit from the targeted drug alpelisib soon after its FDA approval in spring 2019 [40]. Third, another major limitation is the testing of tumors from patients with late stage disease, which limits treatment options and hinders patients from receiving the recommended therapy or from enrolling in a clinical trial. As patients in an advanced cancer situation are often in an unstable health condition, obtaining biopsy material with a good quality of tissue is quite difficult. Our study had 14 (14.7%) technically unsuccessful molecular diagnostics. Moreover, the time between enrolling patients in the study, processing tumor samples, followed by the molecular diagnostics and the MTB case discussion is still rather lengthy in view of the fact that malignancies in late stages tend to evolve at unprecedented speed, while causing deterioration of the general condition and hindering patients from receiving particular therapies, one of the main reasons for the relative low number of implemented therapies (9 out of 34). In this study, molecular profiling and discussion were completed in a clinically reasonable time frame of approximately 4 weeks, which is comparable to the median turnaround times in other studies. Therefore, it is reasonable to expect that introducing molecular profiling at an earlier time point in a patient’s disease trajectory could improve the quality of molecular diagnostics and allow patients to benefit more from a multidisciplinary tailored MTB-based treatment advice. Fourth, another concern is that the current trend of identifying single variables and matching it with an appropriate targeted therapy may be irrelevant for some patients because of the heterogeneous landscape of their cancer. Disease variability among individual tumors causes patients with tumors of similar histology to respond differently to targeted therapies [41–43]. For example, only 60% of lung cancer patients with the p.L858R mutation in the epidermal growth factor receptor gene (EGFR) respond to gefitinib, although all of them are carriers of the exact same mutation in the target gene, indicating that other, yet unknown genetic aberrations may influence the effect of targeted drugs and that the disease course is still unpredictable to a great extent [44]. Fifth, the common use of medicines outside the approved label is controversial. Off-label drug use may represent a danger for patient safety in some cases, but it is sometimes justified from a clinical point of view. Four out of nine (44%) of the implemented recommended therapies in the study “The informative Patient” included off-label drugs; two of these patients (50%) experienced a clinical benefit with a partial response or stabilization lasting over 4 months, while having progressed under last standard treatment. There were several limitations to our study. First, despite a relatively high number of breast and gynecological cancer, the overall number of included patients remains low. Second, our patient cohort presented had a heterogeneous tumor type, making general conclusions relatively difficult. Third, the number of patients with implemented therapies is limited, due to deterioration of patients’ general condition or no access to the recommended targeted drug, as previously reported in other studies. Nevertheless, we do demonstrate feasibility of and patient benefit from a routine MTB at a large comprehensive cancer center. Conclusion The landscape of molecular alterations in breast and gynecological cancers is heterogeneous. Advances in the quality and availability of molecular diagnostics and the number of targeted therapies increase rapidly, offering patients with advanced cancer a variety of new treatment options. MTBs try to bridge the gap in between molecular alterations and matching drugs in a structured manner. The primary objective of the present monocentric study was to estimate, in a real-world setting, the impact of interdisciplinary MTB case discussions for patients with breast and gynecological malignancies. Altogether, on the basis of individual molecular diagnostics, diagnostic and treatment recommendations were made for 45 patients (47.4% of all). Nine out of 34 patients received the recommended treatment. Four out of 9 patients responded with a PFSr > 1.3. Therefore, our results support the approach of matching specific drugs (in- and off-label) to particular genetic aberrations and demonstrate its relevance in breast and gynecological cancers for a small, but clinically relevant group of patients. By providing a multidisciplinary tailored-based treatment advice based on genetic tests, it is now possible for more patients with breast and gynecological malignancies to gain maximum clinical benefit and improve survival of patients with either advanced stage cancer or a rare tumor entity by applying personalized medicine. The MTB strategy, however, needs to be standardized and optimized in order to eliminate major logistical problems such as limited access to targeted agents (often off-label) and clinical trials, as well as patient referral at stage disease that are too late for a beneficial therapeutic intervention. Appendix See Table Table 5 Data supplement # Mutation Tumor entity Treatment recommended in MTB Followed treatment / Line of therapy PFS (months) after start of treatment 1 FGFR1, androgen receptor and CCND1 amplifications Breast 1. CDK4/6 Inhibitor 2. Everolimus 3. androgen receptor blocker 2 CCND1 amplification Breast 1. CDK4/6 Inhibitor 2. Palbociclib + Fulvestrant 3. Everolimus Palbociclib 21 3 ERBB2 mutation Breast Afatinib / Neratinib 4 PTEN deletion; MET mutation Breast 1. NCT03337724 trial 2. Exemestan + Everolimus 5 PIK3CA mutation Breast Everolimus 6 MET Exon 14 mutation Breast Crizotinib 7 MYC, FGFR1 and CCND1 amplifications Breast Everolimus Everolimus 13 8 androgen receptor amplification Breast 1. NCT01945775 / NCT02163694 trial 2. Bicalutamide / Tamoxifen 9 PIK3CA mutation Breast 1. SOLAR-1 / IPATunity130 trial 2. Everolimus 10 ERBB2 amplification Breast Lapatinib, Trastuzumab, Emtansine and Pertuzumab 11 ARID1A and PIK3CA mutations, LMB (4,16 muts/MB) Breast Everolimus Everolimus 12 12 ESR1 mutation, CCND1 amplification Breast Fulvestrant + Everolimus 13 TP53 and NOTCH1 mutations Breast Cyclophosphamid 14 TPM3(7)—NTRK1(10) gene fusion Breast NCT02568267 trial 15 MET Exon 2 mutation Breast Cabozantinib 16 KRAS and 2 PIK3CA mutations Breast lipos. Doxorubicin / Bevacizumab + Temsirolimus/ Everolimus 17 androgen receptor mutation, PIK3CA mutation Breast Everolimus 18 FGFR1, CCND1, EGFR, PIK3CA and PDGFRA amplifications Breast Pazopanib 19 ESR1 and PIK3CA mutations Breast 1. NCT03056755 trial 2. Everolimus 20 p16 high expression and MYC mutation Breast Checkpoint inhibitor Pembrolizumab 59 21 androgen receptor amplification Breast Androgen receptor blocker 22 AKT mutation Breast 1. AKT inhibitors 2. IPATunity130 trial 3. Everolimus 23 SLX4 and TP53 mutations; amplifications: FGFR1, CCND1, FGF19, FGFR3 Breast Pazopanib Pazopanib 12 24 ESR1 mutation Breast Fulvestrant + CDK4/6 Inhibitoren 25 CCND1 and FGFR1 amplifications Breast 1. Everolimus + antihormonal therapy; 2. Dovitinib 26 PIK3CA and ERBB2 mutations, high expression ERBB2 Breast 1. Pertuzumab/ Trastuzumab (+ Everolimus) 2. Neratinib Lapatinib 18 27 FGFR1 amplification Breast antihormonal therapy + Everolimus + Trastuzumab Exemestan + Everolimus + Trastuzumab 4 28 CCND1 amplification Breast 1. Exemestan + Everolimus; 2. NCT-MASTER / TOP-ART trial 29 CCND1 and FGFR1 amplifications Breast 1. Everolimus + Exemestan 2. NCT03517956 trial Everolimus + Exemestan 14 30 KRAS and ERBB2 mutations Ovary NCT02703571 trial 31 ERBB2, MYC, PIK3CA amplifications Ovary Everolimus + Letrozol 32 PIK3CA alteration Cervix Temsirolimus Temsirolimus 32 33 PIK3CA and KRAS mutations, MET gene fusion Cervix 1. Crizotinib 2. Everolimus 34 KRAS, SMAD4 and PTEN mutations Endometrium Everolimus 35 HTB (27 muts/MB) Other 1. Checkpoint inhibitor 2. NCT Master trial 36 EML4-ALK gene fusion Other ALK inhibitor 5. Author contributions ES: Manuscript writing, Data management. BW: Project development, Data collection and management, Manuscript editing. AJ: Data collection, Manuscript editing. JK: Data collection, Manuscript editing. TK: Data collection, Manuscript editing. DM: Data collection, Manuscript editing. MR: Data collection, Manuscript editing. SO: Data collection, Manuscript editing. VH: Project development, Manuscript editing. KHM: Data collection, Manuscript editing. PAG: Data collection, Manuscript editing. AB: Data collection, Manuscript editing. FT: Data collection, Manuscript editing. SM: Manuscript editing, Manuscript editing. NH: Manuscript editing, Manuscript editing. RW: Project development, Data collection and management, Manuscript editing. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest statement CBW received personal and speakers’ fees, reimbursement for travel and accommodation and honoraria for participance in advisory boards from Bayer, Celgene, Ipsen, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta and Taiho and grant support by Roche. AJ received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from Amgen, AstraZeneca, Biocartis, Bristo-Myers Squibb (BMS), Boehringer Ingelheim, Chinese Society for Pathology, German Society for Pathology, European Association for Cancer Research (EACR), International Association for Pathology (IAP), Merck-Serono, Merck-Sharp Dohme (MSD), Quality Initiative in Pathology (QuIP), Roche Pharma, Takeda; JK received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Novartis, Quality Initiative in Pathology (QuIP), Roche Pharma. TK received honoraria and reimbursement for travel and accommodation for participance in advisory boards from Amgen, AstraZeneca, Merck KGaA, MSD, Novartis, Pfizer, Roche; and from speaker's bureau from Merck and Astra Zeneca; from Merck and Roche research funding as well. KHM received honoraria from Celgene, Pfizer, Astellas, Daiichi Sankyo and Otsuka Pharma. AB received honoraria and reimbursement for travel and accommodation for participance in advisory boards from AstraZeneka, Roche and Tesaro. FT received research support, reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Clovis, Medac, PharmaMar, Roche, Tesaro/GSK. SM received research support, advisory board, honoraria and travel expenses from AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Medac, MSD, Novartis, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro. NH received honoraria for lectures and/or consulting from Agendia, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. RW received honoraria for lectures and/or consulting from Agendia, Amgen, Aristo, Astra Zeneca, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. Ethical approval The study received approval of the local ethics committee (study number: 284–10) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to participate and publication: Informed consent was obtained from all individual participants included in the study. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Fatal	ReactionOutcome	CC BY	33277683	19,645,107	2021-05
What was the outcome of reaction 'Off label use'?	NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU. Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months. In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. 284-10 (03.05.2018). Introduction In women, metastatic breast cancer and gynecological malignancies are among the most frequent causes of cancer death. In 2018, there were an estimated 2,088,849 new cases of breast cancer and 626,679 deaths, 569,847 new cases of cervical cancer and 311 365 deaths, and 295,414 new cases of ovarian cancer and 184,799 deaths worldwide. [1] Despite rising overall incidence, mortality rate has steadily decreased owing to early detection and improvements in the therapeutic management of these patients. However, although the development of new drugs, vaccines, and systematic screening programs has improved patients’ outcomes, effective measures to successfully treat metastatic cancer are still missing. With the advent of molecular diagnostics, cancer treatment entered a new era. New techniques of sequencing DNA such as comprehensive genomic profiling (CGP) and hotspot next generation sequencing (NGS) provide tools for deciphering complete genes and later entire genomes at unprecedented speed [2]. These new approaches led to the development of a novel cancer treatment movement, known as precision medicine. By selecting the most effective treatment based on the molecular characteristics of tumor tissues or some other biologic parameters of the malignant disease, precision medicine aims to offer personalized treatment concepts to cancer patients with limited standard of care options. Molecular therapeutic agents (MTA) targeting individual actionable molecular alterations have been successfully developed in the past few years, showing the positive impact of using molecular-based therapy on the cancer patients’ outcome [3–6]. These include the use of growth factor receptor 2 antibody trastuzumab in breast cancer, a tyrosine kinase inhibitor imatinib in myelogenous leukemia associated with the BCR-ABL fusion gene and EGFR tyrosine kinase inhibitors in lung carcinomas [7, 8]. Breast and gynecological cancers constitute a heterogeneous group of malignant diseases associated with multiple genetic alterations [9–11]. In the past few years, a growing number of molecular markers in breast cancer, for example, have been investigated and some of them are now well-established as reliable predictors of prognosis and response to tumor therapy (Fig. 1a). Moreover, many different targeted therapies have been approved for use in breast cancer treatment (Fig. 1b). The recent approval of the PIK3CA specific inhibitor alpelisib has been the most recent example of targeted agents moving into routine care. [12] Treatment with alpelisib was shown to prolong PFS by more than 6 months compared to the control arm. [13]Fig. 1 Predictive factors (a) and treatment-relevant genetic alterations (b) in metastatic breast cancer, German Gynecological Oncology Group. In 2018, AGO was the first international guideline-commission to make recommendations regarding precision medicine in breast cancer. (http://www.ago-online.de) [14] In gynecologic malignancies, MTAs have also been successfully implemented into clinical care. For example, early data from a clinical phase II trial focusing on BRCA-mutated ovarian cancer showed that olaparib as maintenance treatment significantly improved progression-free survival (PFS) in relapsed platinum-sensitive ovarian cancer [15]. In 2018, these data could be transferred to the first line setting when treatment effects of the SOLO1 trial were presented [16]. Due to an impressive PFS improvement and a 70% lower risk of disease progression or death with olaparib compared to placebo, this effect led to the incorporation of PARP inhibitors into the primary treatment of ovarian cancer in 2019 [17]. However, when it comes to other gynecologic malignancies such as endometrial cancer, the development of MTA is delayed in comparison to other malignancies. By detecting potential actionable pathways using molecular diagnostics, it is also possible to assess and treat various cancer types. For example, the ERBB2/PIK3/AKT/mTOR pathway is known for its relevance in breast cancer, but recently a relevant actionable mutation from the same pathway, PIK3R1W624R was also identified in ovarian cancer [18]. Another study suggested that some subtypes of cervical cancers may also benefit from existing ERBB2/PIK3/AKT/mTOR targeted agents [19]. With the rising number of MTAs and considering the heterogeneous molecular profiles of breast cancer and gynecological malignancies, it is reasonable to expect that patients with these malignancies could potentially benefit from implementation of precision oncology based on comprehensive genomic profiling (CGP) into clinical care. Promising early data for such malignancies has been presented in multiple trials. In breast cancer, many reports of such driver alterations have emerged in the past few years, suggesting that patients could profit from precision medicine and targeted therapies [20]. For example, in the SAFIR01 multicenter prospective trial, data of precision medicine benefitting breast cancer patients were presented. 9 out of 43 patients (21%) responded to the recommended targeted therapy with a stable disease lasting over 16 weeks [21]. In ovarian cancer, multiplatform molecular profiling, conducted in a commercially available profiling center, led to a significantly longer post-profiling survival in patients, who were treated with profile-guided targeted agents, in comparison to the control group [22]. With the technical advances in molecular diagnostics and the continuous approval of many targeted therapies, the growing field of precision medicine is constantly expanding and requires optimization. Considering the complexity of precision medicine in oncology, it was reasonable to create a molecular tumor board (MTB) to leverage the knowledge of the many different disciplines involved in oncological treatment and to provide optimal treatment recommendations. In this manuscript, first experiences of the Comprehensive Cancer Center (CCC) LMU Munich Molecular Tumor Board are presented. The aim of this project was to retrospectively measure the impact of MTB discussions and recommendations made by a multidisciplinary tumor board on outcome of patients with breast and gynecological cancers progressing under standard treatment. Detailed information including data on patient characteristics, diagnostic and treatment recommendations, implementation of the recommendations, and outcome of treated patients with breast and gynecological cancers (ovarian, endometrial, cervix, and other type of cancer) are presented. Materials and methods All patients reported here were discussed in the local MTB, which reviewed clinical cases and the respective tumor profiles with the associated actionable alterations. The final result of each MTB case discussion was a report, focused on NGS data and diagnostic and potential diagnostic, and therapeutic alternatives. Thereby, the MTB presented itself as a multidisciplinary team (MDT), which comprised clinical oncologists, pathologists, molecular pathologists, genetic counselors, bioinformaticians, and scientists with expertise in genetic and tumor profiling in diverse cancers. MTB-meetings were held every 2 weeks with the purpose of interpretation and/or translation of the molecular diagnostics’ results into diagnostic and/or treatment recommendations. All patients’ cases were first presented at organ-specific gynecology tumor boards by a team of experienced gyneco-oncologists, who reviewed all the clinical course of every individual patient and discussed if patients were eligible for a MTB discussion. Apart from recent tumor material, recent radiology images and other diagnostic tests were also required for the interdisciplinary setting of the MTB. All treatment recommendations were supported by levels of evidence by using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). The process from enrolling the patient into the study till receiving a recommendation by the MTB is shown in Fig. 2.Fig. 2 MTB, from suggestion to conclusion Patients and patient informed consent All patients discussed (n = 95) were included in the prospective single-center case study, “The informative Patient”, launched in March 2017 at the LMU University Hospital, Munich as a Munich-site part of the DKTK (German Cancer Consortium) program. All enrolled patients suffered from metastatic breast or gynecological cancer which had progressed after at least one line of prior standard treatment and who had no longer access to curative treatment. Prior to inclusion, all participants signed an informed consent that they were informed about potential and limitations that molecular diagnostics could offer for treatment selection and for analysis of their data, further discussion of their case by a multidisciplinary MTB, as well as for collecting follow-up data on the course of disease for research purpose (including requesting patient data from other physicians and institutions). The intention-to-treat (ITT) population consisted of 100 patients. Eventually, five patients were excluded, because of death prior to a treatment recommendation or withdrawal of consent. The data here are based on the results of an ITT population of 95 patients. Molecular pathology Molecular analyses were performed at the Institute of Pathology of the LMU. Appropriate tissue regions were selected histo-morphologically from formalin-fixed paraffin embedded (FFPE)- or fresh frozen tissue. Moreover, liquid biopsies (blood, liquor) were included. In only four patients, analysis had to be repeated due to material constraints. Targeted NGS was performed with the Oncomine Comprehensive Cancer v.3 Panels (Agilent) thereby screening for changes in 161 genes on DNA (SNV, MNV, small ins, del, indels, CNV) and RNA (gene fusions) level. DNA and RNA were isolated using Qiagen's GeneRead DNA FFPE- or RNeasy FFPE-kits, respectively. Nucleic acids (NA; DNA, and RNA) from liquid biopsies were prepared by utilization of the QIAamp Circulating Nucleic Acid Kit. Subsequently, library preparation as first step of NGS was generated by employing Ampliseq Library Plus-, Ampliseq cDNA synthesis-, Ampliseq CD index, Ampliseq Equalizer- together with Ampliseq Comprehensive v3-kits (all Illumina) or DNA- and RNA-Oncomine Comprehensive Panels v3 and Ion AmpliSeq Library-, IonXpress Barcode Adapter-, Ion Library Equalizer-kits together with Ion Chip kits (mostly 550) (all Thermo Fisher), following for each step the respective user manuals. Libraries were run on an Ion Torrent GeneStudio S5 Primer (Thermo Fisher) or Illumina 500 Next Seq (Illumina) NGS machine. Analysis of results was performed with either the Ion-Reporter System (Thermo Fisher) followed by further variant and quality interpretation with a self-made excel tool or annotating VCF-files using wAnnovar (http://wannovar.wglab.org/) [23] together with the self-made python-script PathoMine filtering for clinically relevant mutations. Mutations were judged as relevant on the basis of the key 'interpretation' given in ClinVar [24]. Alterations were confirmed with the Integrated Genomics Viewer (IGV, Broad Institute). The resulting molecular pathological dataset together with data from immunohistochemistry, fluorescence in situ hybridization (FISH), and histo-morphology became part of a comprehensive pathological report which was sent out to the MTB. Data assessment For this analysis, electronic medical records were reviewed for patient characteristics and follow-up. If needed, medical oncologists, gynecologists, and general practitioners were contacted in order to collect follow-up data on treatment course and patient status. Patient characteristics were summarized using descriptive statistics. Follow-up of clinical outcomes was performed to track tumor response to recommended therapies and analyzed by measuring progression-free survival (PFS) of patients, who received the recommended treatment. PFS was calculated from the first day of treatment with the recommended in- or off-label targeted drug until the date of disease progression or death, whichever occurred first, analogous to the Johns Hopkins MTB study and to the Von Hoff et al. study [25]. In order to evaluate the benefit of the treatment recommendation, we then calculated the PFS ratio (PFSr) by comparing the PFS of the recommended treatment and the PFS of the previous therapy of the patients. Cut-off date for data analysis was August 1st, 2019. Results Patient characteristics From March 2017 through March 2019, a total of 95 cases were submitted to the MTB. All patients (n = 95) were females, had an underlying malignant condition, suffered from metastatic disease, and had experienced disease progression under standard treatment. Patients with implemented therapy recommendations had received a median of five (range 2–6) prior therapies for metastatic cancer. The median age at time of the initial MTB presentation was 52 years (range 19–82 years). As shown in Fig. 3, the most frequent tumor type was breast cancer (n = 64, 68%), followed by ovarian cancer (n = 19, 20%). The majority of patients with breast cancer had triple-negative (ER, PR and HER2 negative; n = 30; 46.9%), followed by estrogen receptor (ER) -positive and/or progesterone receptor (PR) -positive, human epidermal growth factor receptor 2 (HER2) -negative (luminal-like) (n = 28; 43.8%), or HER2 positive, ER-negative, PR-negative disease (n = 5; 7.8%) at the time of the MTB case discussion; one patient (1.6%) had triple-positive disease (ER positive and/or PR positive, HER2 positive).Fig. 3 Distribution of the cases discussed at the MTB meeting by tumor entity (n = 95) Characteristics of patients with a molecular profile are reported in Table 1.Table 1 Patient characteristics Covariables Median age at diagnosis 47 years (range 12–80) Age at diagnosis < 30 5 (5.3%) 30–39 27 (28.4%) 40–49 21 (22.1%) 50–59 30 (31.6%) 60–69 8 (8.4%) ≥ 70 4 (4.2%) Median age at MTB case presentation 52 years (range 19–82) Age at MTB case presentation < 30 2 (2.1%) 30–39 19 (20.0%) 40–49 20 (21.1%) 50–59 28 (29.5%) 60–69 18 (18.9%) ≥ 70 8 (8.4%) Molecular profiling Molecular tests using NGS were performed for all 95 patients. Out of the set of mutations from the molecular pathological NGS-analysis, actionable mutations were defined as those matching or informing the use of available targeted agents. Four patients had tumor sequencing performed twice during the course of disease. 81 (85.3%) patients had suitable tissues for multimodal molecular profiling (NGS). All in all, 103 molecular alterations were identified in 55 cases (57.9%). The median number of alterations observed in each sample was one (range 0–6). Out of the 55 patients, 41 (43.2%) had an actionable mutation, which the board reviewed as a potentially targetable. No genomic alterations in the 161 investigated genes were found in 40 (42.1%) analyses, in 14 (14.7%) of which the molecular diagnostics test was technically not successful because of poor DNA quality or insufficient material quality. Although five (5.3%) patients had an actionable mutation, they did not receive a therapy recommendation because of co-morbidities, not meeting trial inclusion criteria, or other requirements for receiving a specific targeted therapy. We discovered mutations in over 30 different genes. Among the patients tested, the most common alterations were as follows: PIK3CA mutation (13/95; 13.7%); ERBB2 mutation (10/95; 10.5%); KRAS mutation (9/95; 9.5%), and CCND1 mutation (9/95; 9.5%). Incidences of genomic alterations by gene and the distribution of molecular alterations by tumor type are shown in Fig. 4.Fig. 4 Frequency of genomic alterations for the different tumor entities (n = 95) Recommendations Among the 55 (57.9%) patients with at least one molecular alteration identified, 41 patients (43.2%) had an actionable alteration, whereas 14 (14.7%) had only non-actionable variants. Eventually, this resulted in 15 diagnostic and 49 treatment recommendations for 45 patients (47.4%). Multiple recommendations were adjusted for 20 (21.1%) patients (multiple recommendation principle). Six patients received a conditional recommendation, which required specific further diagnostics, two of which resulted in a treatment recommendation. Diagnostic recommendations Out of 15 diagnostic recommendations, 10 were pursued. In seven (7.4%) cases, extended genetic analyses were recommended and eventually six (6.3%) of them were performed. Re-biopsies were recommended in 14 cases, when the initial diagnostic tests were technically not successful, which we did not include in the evaluation of the final results. Therapeutic recommendations As shown in Fig. 5, 36 (37.9%) patients were given a therapy recommendation, 14 (14.7%) of whom received more than one treatment suggestion, as their tumor molecular profile revealed more than one actionable mutation. Two (2.1%) patients were excluded from the evaluation of the clinical outcome, as they received the recommended therapy in the period between NGS analysis and MTB treatment recommendation.Fig. 5 Treatment or diagnostic recommendations. Note, all numbers do not add up because some patients are counted in more than one category (e.g., had an actionable alteration for a treatment recommendation and also for diagnostic recommendation or received more than one treatment/ diagnostic recommendation). a Diagram representing the outcome of the molecular diagnostic testing (n = 95). b Breast cancer patients. c Gynecological cancer patients Overall, 9 of 34 therapeutic recommendations were pursued. Of note, in the present cohort, no patient pursued the recommended enrollment in a clinical trial. In-label therapy recommendations were implemented in five cases, whereas off-label recommendations were implemented in four patients. The most common reasons for non-administration of MTB-recommended therapy were deterioration of patients’ physical health condition, early death, no access to the recommended drug therapy, declined reimbursement applications by payer, or patient decision (see Table 2).Table 2 Recommendations (Note, some patients received more than one diagnostic and/or treatment recommendation.) BC GC Patients with min. 1 recommendation No No Diagnostic 8 7 Therapeutic 27 7 No treatment recommendation 30 20 Conditional recommendation 3 3 Referral to organ board 1 Diagnostic recommendations Extended genetic analysis 3 4 PD-L1 Test 2 HR-Status 1 1 Other 5 3 Patients with diagnostic recommendations (n = 15) Implemented 6 4 Non-implemented 2 3 Treatment recommendations Targeted therapy 32 5 Trial inclusion 8 2 Checkpoint inhibition 1 1 Patients with treatment recommendations (n = 36) Implemented 7 1 Non-implemented 22 6 Clinical outcome All patients were included in the registry after multiple standard of care treatments. Out of nine (9.5%) patients following therapy recommendation, 4 (4.2%) showed a state of partial remission or stabilization lasting more than 16 weeks, including two of them receiving off-label therapy recommendation. Comparing PFS of the recommended therapy with the PFS of the previously received systemic treatment, we estimated that four of nine responders receiving MTB-recommended therapies displayed a progression-free survival (PFS) ratio (PFS2/PFS1; PFSr) > 1.3, showing the relevance of the suggested therapies. Two patients responded with an ongoing PFSr. Figure 6 details the actual comparison of PFS on implemented recommended treatment versus PFS on the patient’s last prior treatment.Fig. 6 Comparison of PFS of previous line of therapy (PFS1) and implemented therapy recommendation (PFS2). PFS the period of time between the start of treatment till disease progression/ death More information about the outcome of responding patients is shown in Table 3.Table 3 PFS ratio (PFSr) = ratio of patients’ PFS on the implemented recommended therapy (PFS2) (in this case the recommended in- or off-label targeted drug) to their PFS on the most recent previous line of therapy (standard of care) (PFS1) # Tumor entity Treatment Label PFS2 (weeks) PFS1 (weeks) PFSr 1 Breast Everolimus In 14 81 0.17 2 Breast Everolimus In 12 55 0.22 3 Breast Exemestan + Everolimus + Trastuzumab Off 4 8 0.50 4 Breast Everolimus In 13 13 1.00 5 Breast Pazopanib Off 12 6 2.00 6 Breast Lapatinib In 18 3 6.00 7 Breast Palbociclib In 21 13 1.62 8 Breast Pembrolizumab Off 59 5 11.80 9 Cervix Temsirolimus Off 32 38 0.84 PFSr PFS2/PFS1 See Appendix for details of identified actionable mutations and corresponded treatment recommendations made by the MTB. Discussion We evaluated the clinical consequences of actionable genetic alterations (by NGS) in 95 patients with metastatic breast cancer and gynecological malignancies, part of a pilot monocentric patient registry with the purpose of generating real-world data. Forty-one patients (43.2%) had at least one actionable molecular aberration. The total number of patients with a drug-targetable alteration was 34 (35.7%). Overall, 9 of 34 patients (9.5% of all) received the recommended drug treatment. In a small, but significant group of patients, four out of nine with implemented therapy recommendations (44.4%) experienced a clinical benefit (PFSr > 1.3) lasting over 16 months, a result similar to the one shown by Jameson et al. in cases of patients with metastatic breast cancer, who received personalized therapy recommendations based on multi-omic molecular profiling [26, 27]. Precision medicine offers not only personalized treatment concepts for patients, but also helps us optimize diagnostic and treatment options by identifying biomarkers that are linked to response and resistance to immunotherapy. For instance, in the past few years, the problem of resistance to endocrine therapy has been a point of research. Recently, the key role of the acquisition of ligand-independent ESR1 mutation in breast cancer as a common mechanism of resistance to hormonal therapy was discovered [28]. So far, the precision medicine movement is controversial and has sparked multiple debates. On the one hand, the SHIVA trial (2015), one of the first randomized investigation of precision therapy, was negative for its primary endpoint (progression-free survival [PFS]), as no statistically significant difference in PFS between patients receiving molecularly targeted agents and the control arm was demonstrated [29]. On the other hand, studies recruiting large number of patients, such as MOSCATO 01 (2017) and ProfiLER (2017), suggested that high-throughput genomic analyses (i.e. next-generation sequencing, comprehensive genomic profiling) improve clinical outcome in patients with advanced cancers. However, this approach has only been proven to be beneficial to a small subset of patients so far [30, 31]. As shown in Table 4, studies focusing on precision medicine show different, contradictory results. While in some studies more than 20% of the enrolled patients received the recommended according to molecular profiling treatment, in others the number of patients treated remains very low. These results suggest the need for large data collections in order to improve selection criteria and identify markers that discriminate patients that might benefit most from precision medicine.Table 4 Overview of studies focusing on molecular profiling Author/Study Tumor entity Enrolled patients (n ) MP patients Actionable alterations Implemented therapies—n (% of enrolled) Results Le Tourneau et al. (SHIVA) [29] Solid tumors 741 496 (67%) 293 (40%) 96 (13%) No significant difference in PFS (PFS: 2.3 vs 2.0 p = .41), hazard ratio for death or disease progression, 0.88 (95% CI 0.65–1.19) Stockley et al. (IMPACT/COMPACT) [45] Solid tumors 1893 1640 (87%) 187 (10%) 84 (5%) ORR: 19% in genotype-matched group vs 9% in unmatched group, p = 0.61 Massard et al. (MOSCATO-01) [30] Solid tumors 1035 843 (81%) 411 (40%) 199 (24%) ORR: 11%, SD 52%, PFSr > 1.3: 63/193 (33% of all treated patients or 7% of all enrolled patients) Trédan et al. (PROFILER) [31] Solid tumors 2579 1980 (77%) 1032 (40%) 163 (6%) ORR: 0.9% of all patients Rodon et al. (WINTHER) [46] Solid tumors 303 303 (100%) 25 (89%) 107 (35%) PFSr > 1.5: 22% of the patients with MP-based treatment Hoefflin et al. [47] Solid tumors 198 n.a 104 (53%) 33 (17%) PR: 11/33 (33.3% of all treated patients or 5.5% of all enrolled patients) SD: 8/33 (24.2% of all treated patients or 4% of all enrolled patients) André et al. (SAFIR01/UNICANCER) [21] Breast cancer 423 299 (71%) 195 (46%) 55 (13%) ORR:4 patients had a partial response and 9 had SD > 16 weeks (3% of all patients) Parker et al. [27] Breast cancer 43 43 (100%) 40 (93%) 17 (40%) 7 patients (41% of all treated patients or 16% of all enrolled patients) achieved SD or PR MP molecular profiled, PFS progression-free survival, ORR overall response rate, SD stable disease, PR disease progression, n.a. not available Although molecular targeted agents themselves are more precise than standard cytotoxic agents, clinical evidence for a significant better outcome associated with MTAs is still missing, as the access to targeted therapies remains limited, making collecting data regarding their efficacy difficult. In order to achieve their implementation in clinical care, a re-assessment of the standards of evidence sufficient to prove the benefit of precision cancer therapies is needed [32]. New evidence suggests that appropriately conducted real-world data studies have the potential to support regulatory decisions in the absence of RCT data [33]. Based on initial results of the CCC LMU Munich, patients of various tumor entities benefit from extended molecular diagnostics and their implementation in clinical care [34]. Recently, many studies have described the positive effect of MTB case discussions for particular groups of patients with advanced solid cancers. However, there is not enough evidence for the utility of MTB decisions for patients with breast and gynecological malignancies. The world of precision medicine is constantly evolving, and new targeted therapies are being developed and approved, enabling more and more patients (with up to this point of time not actionable mutation) to receive targeted therapies. For example, in spring 2019, the Food and Drug Administration of the USA (FDA) approved the PIK3CA inhibitor alpelisib in combination with endocrine therapy for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. The availability of this drug after start of the Managed Access Program in our clinic could have resulted in five further therapy recommendations in our MTB cohort, showing the need of identifying such alterations in cancer patients. The rising number of active targetable mutations affects the complexity of the results, making their interpretation a challenge for many oncologists. In 2014, Gray et al. conducted a study, which evaluated cancer physicians’ ability of using multiplex tumor genomic testing and showed that many physicians lack confidence in interpreting complex genomic test results as well as in incorporating them into practice [35]. Thus, we see great potential in establishing the combination of molecular diagnostic tests and a subsequent case discussion by a multidisciplinary molecular board team not only as a routine for cancer patients but also as a training platform and a knowledge-expanding approach for oncologists to help guide their decisions. However, precision oncology faces some challenges, which delay its widespread translation into clinical practice. Critics of the incorporation of NGS and similar methods into clinical practice express following concerns: First, the significant cost of molecular diagnostics and targeted drugs is still a great disadvantage. While prices of next-generation sequencing technologies are dropping from about $3 billion in the year 2000 and to $5000 today, the selection of molecular targeted agents is still enormously expensive [36]. As the price of precision medicine is still rather high for most patients, it is now crucial to also evaluate its cost-effectiveness in order to support its translation into clinical practice, for example in the setting of clinical trials and research programs [37]. Second, logistical problems causing limited access to targeted drugs and clinical trials for biomarker-positive patients represent another major problem. This is mainly due to the absence of reimbursement for drugs beyond their labelled indication. As a consequence, in order to receive the required, often off-label drug, patients need to be enrolled within active clinical trials or are required to cover the costs themselves or to file an application for reimbursement by the competent health insurance prior to treatment initiation. Clinical trials often have strict inclusion criteria and are, therefore, not easily accessible to many patients. As shown in the SAFIR01 trial, only a small number of patients benefit from personalized therapies mostly due to drug access problems. This problem could be solved by establishing a portfolio of early phase clinical basket trials or by early-access-programs [38]. Recent studies suggest that the implementation of a MTB improves access to targeted therapy [39]. As seen in our clinic, the early-access-program that we started in November 2019 enabled many patients with a PIK3CA mutation to derive benefit from the targeted drug alpelisib soon after its FDA approval in spring 2019 [40]. Third, another major limitation is the testing of tumors from patients with late stage disease, which limits treatment options and hinders patients from receiving the recommended therapy or from enrolling in a clinical trial. As patients in an advanced cancer situation are often in an unstable health condition, obtaining biopsy material with a good quality of tissue is quite difficult. Our study had 14 (14.7%) technically unsuccessful molecular diagnostics. Moreover, the time between enrolling patients in the study, processing tumor samples, followed by the molecular diagnostics and the MTB case discussion is still rather lengthy in view of the fact that malignancies in late stages tend to evolve at unprecedented speed, while causing deterioration of the general condition and hindering patients from receiving particular therapies, one of the main reasons for the relative low number of implemented therapies (9 out of 34). In this study, molecular profiling and discussion were completed in a clinically reasonable time frame of approximately 4 weeks, which is comparable to the median turnaround times in other studies. Therefore, it is reasonable to expect that introducing molecular profiling at an earlier time point in a patient’s disease trajectory could improve the quality of molecular diagnostics and allow patients to benefit more from a multidisciplinary tailored MTB-based treatment advice. Fourth, another concern is that the current trend of identifying single variables and matching it with an appropriate targeted therapy may be irrelevant for some patients because of the heterogeneous landscape of their cancer. Disease variability among individual tumors causes patients with tumors of similar histology to respond differently to targeted therapies [41–43]. For example, only 60% of lung cancer patients with the p.L858R mutation in the epidermal growth factor receptor gene (EGFR) respond to gefitinib, although all of them are carriers of the exact same mutation in the target gene, indicating that other, yet unknown genetic aberrations may influence the effect of targeted drugs and that the disease course is still unpredictable to a great extent [44]. Fifth, the common use of medicines outside the approved label is controversial. Off-label drug use may represent a danger for patient safety in some cases, but it is sometimes justified from a clinical point of view. Four out of nine (44%) of the implemented recommended therapies in the study “The informative Patient” included off-label drugs; two of these patients (50%) experienced a clinical benefit with a partial response or stabilization lasting over 4 months, while having progressed under last standard treatment. There were several limitations to our study. First, despite a relatively high number of breast and gynecological cancer, the overall number of included patients remains low. Second, our patient cohort presented had a heterogeneous tumor type, making general conclusions relatively difficult. Third, the number of patients with implemented therapies is limited, due to deterioration of patients’ general condition or no access to the recommended targeted drug, as previously reported in other studies. Nevertheless, we do demonstrate feasibility of and patient benefit from a routine MTB at a large comprehensive cancer center. Conclusion The landscape of molecular alterations in breast and gynecological cancers is heterogeneous. Advances in the quality and availability of molecular diagnostics and the number of targeted therapies increase rapidly, offering patients with advanced cancer a variety of new treatment options. MTBs try to bridge the gap in between molecular alterations and matching drugs in a structured manner. The primary objective of the present monocentric study was to estimate, in a real-world setting, the impact of interdisciplinary MTB case discussions for patients with breast and gynecological malignancies. Altogether, on the basis of individual molecular diagnostics, diagnostic and treatment recommendations were made for 45 patients (47.4% of all). Nine out of 34 patients received the recommended treatment. Four out of 9 patients responded with a PFSr > 1.3. Therefore, our results support the approach of matching specific drugs (in- and off-label) to particular genetic aberrations and demonstrate its relevance in breast and gynecological cancers for a small, but clinically relevant group of patients. By providing a multidisciplinary tailored-based treatment advice based on genetic tests, it is now possible for more patients with breast and gynecological malignancies to gain maximum clinical benefit and improve survival of patients with either advanced stage cancer or a rare tumor entity by applying personalized medicine. The MTB strategy, however, needs to be standardized and optimized in order to eliminate major logistical problems such as limited access to targeted agents (often off-label) and clinical trials, as well as patient referral at stage disease that are too late for a beneficial therapeutic intervention. Appendix See Table Table 5 Data supplement # Mutation Tumor entity Treatment recommended in MTB Followed treatment / Line of therapy PFS (months) after start of treatment 1 FGFR1, androgen receptor and CCND1 amplifications Breast 1. CDK4/6 Inhibitor 2. Everolimus 3. androgen receptor blocker 2 CCND1 amplification Breast 1. CDK4/6 Inhibitor 2. Palbociclib + Fulvestrant 3. Everolimus Palbociclib 21 3 ERBB2 mutation Breast Afatinib / Neratinib 4 PTEN deletion; MET mutation Breast 1. NCT03337724 trial 2. Exemestan + Everolimus 5 PIK3CA mutation Breast Everolimus 6 MET Exon 14 mutation Breast Crizotinib 7 MYC, FGFR1 and CCND1 amplifications Breast Everolimus Everolimus 13 8 androgen receptor amplification Breast 1. NCT01945775 / NCT02163694 trial 2. Bicalutamide / Tamoxifen 9 PIK3CA mutation Breast 1. SOLAR-1 / IPATunity130 trial 2. Everolimus 10 ERBB2 amplification Breast Lapatinib, Trastuzumab, Emtansine and Pertuzumab 11 ARID1A and PIK3CA mutations, LMB (4,16 muts/MB) Breast Everolimus Everolimus 12 12 ESR1 mutation, CCND1 amplification Breast Fulvestrant + Everolimus 13 TP53 and NOTCH1 mutations Breast Cyclophosphamid 14 TPM3(7)—NTRK1(10) gene fusion Breast NCT02568267 trial 15 MET Exon 2 mutation Breast Cabozantinib 16 KRAS and 2 PIK3CA mutations Breast lipos. Doxorubicin / Bevacizumab + Temsirolimus/ Everolimus 17 androgen receptor mutation, PIK3CA mutation Breast Everolimus 18 FGFR1, CCND1, EGFR, PIK3CA and PDGFRA amplifications Breast Pazopanib 19 ESR1 and PIK3CA mutations Breast 1. NCT03056755 trial 2. Everolimus 20 p16 high expression and MYC mutation Breast Checkpoint inhibitor Pembrolizumab 59 21 androgen receptor amplification Breast Androgen receptor blocker 22 AKT mutation Breast 1. AKT inhibitors 2. IPATunity130 trial 3. Everolimus 23 SLX4 and TP53 mutations; amplifications: FGFR1, CCND1, FGF19, FGFR3 Breast Pazopanib Pazopanib 12 24 ESR1 mutation Breast Fulvestrant + CDK4/6 Inhibitoren 25 CCND1 and FGFR1 amplifications Breast 1. Everolimus + antihormonal therapy; 2. Dovitinib 26 PIK3CA and ERBB2 mutations, high expression ERBB2 Breast 1. Pertuzumab/ Trastuzumab (+ Everolimus) 2. Neratinib Lapatinib 18 27 FGFR1 amplification Breast antihormonal therapy + Everolimus + Trastuzumab Exemestan + Everolimus + Trastuzumab 4 28 CCND1 amplification Breast 1. Exemestan + Everolimus; 2. NCT-MASTER / TOP-ART trial 29 CCND1 and FGFR1 amplifications Breast 1. Everolimus + Exemestan 2. NCT03517956 trial Everolimus + Exemestan 14 30 KRAS and ERBB2 mutations Ovary NCT02703571 trial 31 ERBB2, MYC, PIK3CA amplifications Ovary Everolimus + Letrozol 32 PIK3CA alteration Cervix Temsirolimus Temsirolimus 32 33 PIK3CA and KRAS mutations, MET gene fusion Cervix 1. Crizotinib 2. Everolimus 34 KRAS, SMAD4 and PTEN mutations Endometrium Everolimus 35 HTB (27 muts/MB) Other 1. Checkpoint inhibitor 2. NCT Master trial 36 EML4-ALK gene fusion Other ALK inhibitor 5. Author contributions ES: Manuscript writing, Data management. BW: Project development, Data collection and management, Manuscript editing. AJ: Data collection, Manuscript editing. JK: Data collection, Manuscript editing. TK: Data collection, Manuscript editing. DM: Data collection, Manuscript editing. MR: Data collection, Manuscript editing. SO: Data collection, Manuscript editing. VH: Project development, Manuscript editing. KHM: Data collection, Manuscript editing. PAG: Data collection, Manuscript editing. AB: Data collection, Manuscript editing. FT: Data collection, Manuscript editing. SM: Manuscript editing, Manuscript editing. NH: Manuscript editing, Manuscript editing. RW: Project development, Data collection and management, Manuscript editing. Funding Open Access funding enabled and organized by Projekt DEAL. Compliance with ethical standards Conflict of interest statement CBW received personal and speakers’ fees, reimbursement for travel and accommodation and honoraria for participance in advisory boards from Bayer, Celgene, Ipsen, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta and Taiho and grant support by Roche. AJ received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from Amgen, AstraZeneca, Biocartis, Bristo-Myers Squibb (BMS), Boehringer Ingelheim, Chinese Society for Pathology, German Society for Pathology, European Association for Cancer Research (EACR), International Association for Pathology (IAP), Merck-Serono, Merck-Sharp Dohme (MSD), Quality Initiative in Pathology (QuIP), Roche Pharma, Takeda; JK received honoraria and reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Novartis, Quality Initiative in Pathology (QuIP), Roche Pharma. TK received honoraria and reimbursement for travel and accommodation for participance in advisory boards from Amgen, AstraZeneca, Merck KGaA, MSD, Novartis, Pfizer, Roche; and from speaker's bureau from Merck and Astra Zeneca; from Merck and Roche research funding as well. KHM received honoraria from Celgene, Pfizer, Astellas, Daiichi Sankyo and Otsuka Pharma. AB received honoraria and reimbursement for travel and accommodation for participance in advisory boards from AstraZeneka, Roche and Tesaro. FT received research support, reimbursement for travel and accommodation for participance in advisory boards and from speaker's bureau from AstraZeneca, Clovis, Medac, PharmaMar, Roche, Tesaro/GSK. SM received research support, advisory board, honoraria and travel expenses from AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Medac, MSD, Novartis, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro. NH received honoraria for lectures and/or consulting from Agendia, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. RW received honoraria for lectures and/or consulting from Agendia, Amgen, Aristo, Astra Zeneca, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. Ethical approval The study received approval of the local ethics committee (study number: 284–10) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to participate and publication: Informed consent was obtained from all individual participants included in the study. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Fatal	ReactionOutcome	CC BY	33277683	19,645,107	2021-05
What was the administration route of drug 'TOCILIZUMAB'?	Exacerbation of Ulcerative Colitis with Tocilizumab: A Report of Two Cases, One with Takayasu Arteritis and the Other with Relapsing Polychondritis. Tocilizumab (TCZ), a biologic that blocks the signal transduction of interleukin-6, has been used for the treatment of various autoimmune diseases. Many of these cases are sometimes complicated by ulcerative colitis (UC). However, the effect of TCZ on UC is unclear. We experienced two cases with concomitant UC that were treated with TCZ, one for Takayasu arteritis (TAK) and the other for relapsing polychondritis (RP). TCZ did not improve UC in either of these cases. TCZ might have adverse effects on the intestinal tract, since interleukin-6 signaling plays an important role in intestinal epithelium maintenance. Treatment with TCZ should therefore be carefully provided in patients complicated with UC. Introduction With the advent of biologics in recent years, the outcomes of autoimmune diseases and inflammatory bowel diseases, such as Takayasu arteritis (TAK), relapsing polychondritis (RP) and ulcerative colitis (UC) have greatly improved. TAK, RP and UC are all inflammatory diseases of unknown etiology, which might involve autoimmune mechanisms. These diseases involve large vessels, cartilage and colorectal mucosa, respectively, as the focus of inflammation, and each can cause serious or fatal complications. Hence, their control is essential. However, there are refractory cases of these conditions, in which remission cannot be induced even with the combination of steroids and immunosuppressive agents. The biologic tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, that exerts strong anti-inflammatory effects by blocking the signaling of IL-6, a typical proinflammatory cytokine. TCZ has become one of the mainstays in the treatment of TAK, because it is expected to reduce steroid dose and induce remission in patients who are refractory to previous treatment (1). In RP as well, the effectiveness of various biologics, including TCZ, has been reported (2). Additionally, the status of biologics in the treatment of UC has been well established prior to their use for TAK and RP (3). Clinically, TAK and UC are often seen in the same patient, as is UC and RP (4,5). Therefore, there might be several opportunities to use TCZ in patients who also have UC. However, since the biologics usually used as the first line therapy for UC include tumor necrosis factor inhibitors, there are only few reports of cases of UC treated with TCZ. Hence, the safety and efficacy of TCZ for UC is currently unknown. We herein report two cases that were treated with TCZ, one for TAK and the other for RP, both of which were complicated with UC, along with a review of the relevant literature. Case Reports Case 1 A 17-year-old woman was admitted to our hospital with fever, diarrhea and melena. The blood pressure in her left arm (74/54 mmHg) was lower than in the right (108/60 mmHg), and computed tomography (CT) showed occlusion of the subclavian artery and thickening of the vascular wall in the aortic arch and the common carotid arteries bilaterally. Additionally, colonoscopy revealed mucosal edema and erosion of the entire colon, leading to a diagnosis of TAK and UC (Fig. 1). Her partial Mayo score (pMS), a simplified UC activity measure, was evaluated as 9 at this time. High dose prednisolone (PSL) therapy (1 mg/kg/day) and 5-aminosalicylate were started, which led to remission and her discharge from the hospital, although the PSL dose could not be reduced to less than 17 mg orally daily due to TAK relapse with steroid reduction, despite combination treatment consisting of steroid therapy with tacrolimus (TAC) and methotrexate (MTX). No diarrhea or hematochezia were observed during this period, the disease activity of UC seemed to have passed at a low level. After about a year and a half, TCZ became available for TAK in Japan. Therefore, on day 502 after her initial visit, we started the intradermal injection of 162 mg TCZ once every two weeks. Since TCZ improved vasculitis, we once again attempted to reduce the steroid dose. However, the UC worsened with reduction of PSL, although TAK activity remained low. Positron emission tomography (PET) showed little fluorodeoxyglucose (FDG) uptake in the main artery, but with a high accumulation from the descending colon to the rectum; the maximum standardized uptake value (SUVmax) was 9.7 on day 800 after her initial visit. Her pMS was 5 at this time. We continued TCZ therapy after adjusting the steroid dose and immunosuppressive agents for 6 months. As a result, the treatment was maintained for about three months as described below: PSL 10 mg daily, TAC 8 mg daily, and MTX 14 mg weekly. The steroid dosage was not increased at this stage because she did not give her consent. Subsequently, a second PET performed on day 947 after her initial presentation showed no satisfactory effect on the UC. Her pMS remained at 5-6, which was interpreted as no clinical improvement. Hence, we discontinued TCZ and switched to infliximab (IFX) 5 mg/kg, which led to an improvement in her gastrointestinal symptoms without any exacerbation of TAK. The FDG uptake by the colon was also reduced. Her pMS decreased to 1. The clinical course of this case is shown below (Fig. 2) IFX was administered at two, four and eight weeks after the first dose, and then every eight weeks thereafter. Figure 1. Findings of enhanced CT, CT-angiography and colonoscopy in case 1. Enhanced CT scan showed vessel wall thickening in bilateral common carotid arteries, and the left subclavian artery was completely occluded, as seen on CT-angiography (a, b). Colonoscopy revealed mucosal edema and erosion of the entire colon, leading to ulcerative colitis (c, d). Figure 2. Clinical course of case 1. TCZ was started on day 502 after the initial visit, and PET-CT was performed on days 800, 947 and 1122. Colonoscopy was also performed about one week before or after each PET-CT scan. TCZ improved vasculitis, but was not effective for colitis. TCZ failed to reduce pMS, and PET-CT showed no reduction in SUVmax of the descending colon to rectum. Conversely, IFX improved both clinical symptoms and SUVmax of the descending colon to rectum, without relapse of TAK. 5-ASA: 5-aminosalicylate, AAo: ascending aorta, CRP: C-reactive protein, D to R: descending colon to rectum, IFX: infliximab, Lt. CCA: left common carotid artery, MTX: methotrexate, Others: other immunosuppressive agents, PET: positron emission tomography, pMS: partial Mayo score, TAC: tacrolimus, TCZ: tocilizumab Case 2 A 72-year-old man was admitted for a fever of unknown origin. Bilateral auricular redness and saddle nose were observed. He also suffered from polyarthralgia and swelling, which seemed to be consistent with rheumatoid arthritis. There was no abdominal pain at this time, but diarrhea was observed. Contrast-enhanced CT did not reveal any significant findings other than multiple diverticula in the sigmoid colon. Auricular cartilage biopsy was performed and RP was diagnosed. High dose PSL (1.2 mg/kg) led to an immediate improvement in inflammation, and arthralgia and diarrhea also disappeared. However, it relapsed when the PSL dose was reduced to 8 mg daily. Arthralgia also recurred along with the inflammation. Cyclosporine A therapy was added, but it could not be continued due to renal impairment. Since a previous report described the successful treatment of RP with TCZ (2), and our patient's arthritis also met ACR/EULAR criteria of rheumatoid arthritis (6), TCZ was started. As in the previous case, in our case as well, TCZ was effective in treating the chondritis and arthritis. After four weeks of therapy, however, he developed diarrhea, melena and abdominal pain. Colonoscopy showed diffuse erosions and multiple ulcers from the rectum to sigmoid colon. A mucosal biopsy showed non-specific inflammatory findings consistent with UC. No intranuclear injection bodies were observed on Hematoxylin & Eosin staining, and immunohistochemistry showed no evidence of Cytomegalovirus (CMV)infection (Fig. 3a-d). CMV-DNA was not detected by apolymerase chain reaction testing of biopsy tissue. Stool cultures failed to isolate any significant pathogenic microorganisms, including Clostridium difficile. Glutamate dehydrogenase antigen and toxin A/B of Clostridium difficile in the stool were also undetectable. A diagnosis of UC was made, and high dose PSL with 5-aminosalicylate (4,800 mg daily) therapy was started and TCZ was discontinued. However, ten days after commencing treatment, perforation of the sigmoid colon occurred, and total proctocolectomy was performed. The resected specimen showed typical evidence of pancolitis, and UC was definitively diagnosed (Fig. 3e-h). Figure 3. Findings of colonoscopy and the resected specimen in case 2. a: Colonoscopy findings of the sigmoid colon. b: Microscopic findings, low-power field, Hematoxylin and Eosin (H&E) staining. c: High power field of b. d: Immunohistochemistry study for Cytomegalovirus. Colonoscopy showed diffuse erosions and multiple ulcers from the rectum to sigmoid colon (a). Microscopic findings showed nonspecific inflammation, mainly in the mucosa. There were no nuclear inclusions on H&E staining and no evidence of CMV infection in immunohistochemistry. e: The resected specimen of the whole colon. f: The site of perforation in the sigmoid colon (white arrow). g: Microscopic findings of the colon mucosa, H&E staining, high-power field. h: Microscopic findings at the site of perforation, H&E staining, low-power field. The resected specimen showed perforation of the sigmoid colon and diffuse erosion throughout the entire colon. The residual mucosa showed the findings of pseudopolyps (e, f). Microscopic evaluation showed marked inflammatory cell infiltration and crypt abscesses, consistent with typical UC (g, h). The site of perforation was infiltrated with inflammatory cells in all layers, but it was not possible to determine whether it was consistent with diverticula. Discussion UC is an inflammatory bowel disease of the colonic mucosa that causes multiple erosions and ulcers. Although its etiology remains unclear, it has been suggested to be related to the intestinal microbiome, hereditary factors and malfunction of the immune system. Various indicators are used to measure UC activity, including IL-6. According to previous reports, the IL-6 levels in the serum and colonic mucosa of UC patients increase in association with the disease activity (7,8). Hence, TCZ seems effective in the treatment of UC. However, our cases did not experience any improvement with TCZ. In case 1, UC was improved by changing TCZ to IFX without increasing the dose of steroids and immunosuppressive agents. In case 2 as well, while TCZ was effective for the chondritis, symptoms of UC became apparent and worsened after he started TCZ. Although these results seem to contradict the theory related to the efficacy of TCZ for UC, cases similar to ours have been reported. Atreya et al. reported a case of rheumatoid arthritis with UC that was exacerbated following treatment with TCZ (9). There have also been reports of multiple gastrointestinal ulcer complications other than UC due to TCZ (10,11). As shown in these cases, TCZ appears to induce some kind of intestinal toxicity, which can be explained by the fact that TCZ inhibits one of the non-inflammatory effects of IL-6, namely, intestinal mucosal protection. IL-6 is a pleiotropic cytokine that activates not only the inflammatory response, but also hematopoiesis, angiogenesis and other physiological processes. It is also known to be an important cytokine for tissue regeneration and repair (12). Several reports of murine studies showed that IL-6 signaling plays an essential role in proliferation and maintenance of the intestinal epithelium. According to Jin et al., administration of IL-6 causes intestinal epithelial proliferation that increases intestinal volume and reduces reperfusion injury after ischemia. In contrast, IL-6 deficient mice showed impaired intestinal epithelial repair following damage by 5-fluorouracil (13). Additionally, Tebbutt et al. showed that IL-6 deficient mice had an increased risk of epithelial erosion and mortality compared to wild type mice with dextran sodium sulfate -induced colitis, in a mouse model of UC (14). IL-6 contributes to tissue repair by binding to the IL-6 receptor expressed on cell membranes (mIL-6R) and activating the STAT-3 pathway, via a process called classic signaling. On the other hand, IL-6 also forms a complex with the soluble IL-6 receptor (sIL-6R) that drifts in serum, and induces other signals via glycoprotein 130 (gp130) on the cell membrane, called trans-signaling, which activates the immune system and causes inflammation (15). TCZ exerts anti-inflammatory effects by inhibiting trans-signaling, but since it has a similar affinity for both mIL-6R and sIL-6R, it is expected that intestinal epithelial regeneration is also impaired (16). In our cases, we considered that the mucosal regeneration dysfunction was more problematic than the anti-inflammatory effect of TCZ, leading to a persistence of the mucosal damage and a worsening of inflammation. Previously, the possibility of adverse effects of TCZ on the intestine has been discussed, and TCZ has been known to carry a greater risk for lower gastrointestinal perforation as compared to non-steroidal anti-inflammatory drugs and other biologics (17,18). Patients with diverticula are considered to be particularly at risk because they are inherently prone to diverticulitis, and there is also a warning about this on the medical package insert (19). This is because of the strong anti-inflammatory effect of TCZ, which can exacerbate infection and mask its symptoms, thereby delaying disease detection. Additionally, it has also been hypothesized that the adipose tissue accumulates locally to cover inflamed diverticula, and this response is prevented by inhibiting IL-6 signaling (20-22). In our opinion, in addition to these factors, delayed wound healing due to classic signaling inhibition might be involved in the adverse effects of TCZ on the intestines. UC is generally less likely to cause perforation than other inflammatory bowel diseases, with an estimated incidence of about 3%. Approximately 70% of perforation cases have been reported to be associated with toxic megacolon (23,24), but in our case 2, there was no evidence of toxic megacolon. Since the perforation point was deeply ulcerated, it was unclear histologically or grossly whether the perforation was consistent with diverticula. It is possible that a diverticulum was perforated, as is the known theory, but if not, perforation is a relatively rare complication of UC, as mentioned above. Our experience suggests that TCZ might be associated with a perforation risk in patients with UC. Our cases suggest that TCZ has the potential to cause adverse effects on the intestinal mucosa, and it is therefore considered to be a risk factor for UC with TCZ therapy. Certainly, some cases in which TCZ treatment improved UC, as opposed to our cases and those discussed above, have been reported (25-28). The contradictory results seem to be due to the balance between the disadvantages of inhibiting classic-signaling and the benefits of blocking trans-signaling. However, patient background factors that might improve or exacerbate the disease remain unknown. As in case 2, UC is a disease that must be managed with care, because exacerbations of the disease might require emergency surgery or have serious consequences. Although the effect of TCZ on UC has not been reported in sufficient numbers to be conclusive, it should be used with caution given its potential for causing an exacerbation of the disease. Conclusion TCZ therapy should be administered with care in patients complicated with UC, because it can worsen their intestinal condition. Written informed consent was obtained from both patients for publication of this article. The authors state that they have no Conflict of Interest (COI).	Subcutaneous	DrugAdministrationRoute	CC BY-NC-ND	33281154	18,645,469	2021-05-15
What was the dosage of drug 'TOCILIZUMAB'?	Exacerbation of Ulcerative Colitis with Tocilizumab: A Report of Two Cases, One with Takayasu Arteritis and the Other with Relapsing Polychondritis. Tocilizumab (TCZ), a biologic that blocks the signal transduction of interleukin-6, has been used for the treatment of various autoimmune diseases. Many of these cases are sometimes complicated by ulcerative colitis (UC). However, the effect of TCZ on UC is unclear. We experienced two cases with concomitant UC that were treated with TCZ, one for Takayasu arteritis (TAK) and the other for relapsing polychondritis (RP). TCZ did not improve UC in either of these cases. TCZ might have adverse effects on the intestinal tract, since interleukin-6 signaling plays an important role in intestinal epithelium maintenance. Treatment with TCZ should therefore be carefully provided in patients complicated with UC. Introduction With the advent of biologics in recent years, the outcomes of autoimmune diseases and inflammatory bowel diseases, such as Takayasu arteritis (TAK), relapsing polychondritis (RP) and ulcerative colitis (UC) have greatly improved. TAK, RP and UC are all inflammatory diseases of unknown etiology, which might involve autoimmune mechanisms. These diseases involve large vessels, cartilage and colorectal mucosa, respectively, as the focus of inflammation, and each can cause serious or fatal complications. Hence, their control is essential. However, there are refractory cases of these conditions, in which remission cannot be induced even with the combination of steroids and immunosuppressive agents. The biologic tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, that exerts strong anti-inflammatory effects by blocking the signaling of IL-6, a typical proinflammatory cytokine. TCZ has become one of the mainstays in the treatment of TAK, because it is expected to reduce steroid dose and induce remission in patients who are refractory to previous treatment (1). In RP as well, the effectiveness of various biologics, including TCZ, has been reported (2). Additionally, the status of biologics in the treatment of UC has been well established prior to their use for TAK and RP (3). Clinically, TAK and UC are often seen in the same patient, as is UC and RP (4,5). Therefore, there might be several opportunities to use TCZ in patients who also have UC. However, since the biologics usually used as the first line therapy for UC include tumor necrosis factor inhibitors, there are only few reports of cases of UC treated with TCZ. Hence, the safety and efficacy of TCZ for UC is currently unknown. We herein report two cases that were treated with TCZ, one for TAK and the other for RP, both of which were complicated with UC, along with a review of the relevant literature. Case Reports Case 1 A 17-year-old woman was admitted to our hospital with fever, diarrhea and melena. The blood pressure in her left arm (74/54 mmHg) was lower than in the right (108/60 mmHg), and computed tomography (CT) showed occlusion of the subclavian artery and thickening of the vascular wall in the aortic arch and the common carotid arteries bilaterally. Additionally, colonoscopy revealed mucosal edema and erosion of the entire colon, leading to a diagnosis of TAK and UC (Fig. 1). Her partial Mayo score (pMS), a simplified UC activity measure, was evaluated as 9 at this time. High dose prednisolone (PSL) therapy (1 mg/kg/day) and 5-aminosalicylate were started, which led to remission and her discharge from the hospital, although the PSL dose could not be reduced to less than 17 mg orally daily due to TAK relapse with steroid reduction, despite combination treatment consisting of steroid therapy with tacrolimus (TAC) and methotrexate (MTX). No diarrhea or hematochezia were observed during this period, the disease activity of UC seemed to have passed at a low level. After about a year and a half, TCZ became available for TAK in Japan. Therefore, on day 502 after her initial visit, we started the intradermal injection of 162 mg TCZ once every two weeks. Since TCZ improved vasculitis, we once again attempted to reduce the steroid dose. However, the UC worsened with reduction of PSL, although TAK activity remained low. Positron emission tomography (PET) showed little fluorodeoxyglucose (FDG) uptake in the main artery, but with a high accumulation from the descending colon to the rectum; the maximum standardized uptake value (SUVmax) was 9.7 on day 800 after her initial visit. Her pMS was 5 at this time. We continued TCZ therapy after adjusting the steroid dose and immunosuppressive agents for 6 months. As a result, the treatment was maintained for about three months as described below: PSL 10 mg daily, TAC 8 mg daily, and MTX 14 mg weekly. The steroid dosage was not increased at this stage because she did not give her consent. Subsequently, a second PET performed on day 947 after her initial presentation showed no satisfactory effect on the UC. Her pMS remained at 5-6, which was interpreted as no clinical improvement. Hence, we discontinued TCZ and switched to infliximab (IFX) 5 mg/kg, which led to an improvement in her gastrointestinal symptoms without any exacerbation of TAK. The FDG uptake by the colon was also reduced. Her pMS decreased to 1. The clinical course of this case is shown below (Fig. 2) IFX was administered at two, four and eight weeks after the first dose, and then every eight weeks thereafter. Figure 1. Findings of enhanced CT, CT-angiography and colonoscopy in case 1. Enhanced CT scan showed vessel wall thickening in bilateral common carotid arteries, and the left subclavian artery was completely occluded, as seen on CT-angiography (a, b). Colonoscopy revealed mucosal edema and erosion of the entire colon, leading to ulcerative colitis (c, d). Figure 2. Clinical course of case 1. TCZ was started on day 502 after the initial visit, and PET-CT was performed on days 800, 947 and 1122. Colonoscopy was also performed about one week before or after each PET-CT scan. TCZ improved vasculitis, but was not effective for colitis. TCZ failed to reduce pMS, and PET-CT showed no reduction in SUVmax of the descending colon to rectum. Conversely, IFX improved both clinical symptoms and SUVmax of the descending colon to rectum, without relapse of TAK. 5-ASA: 5-aminosalicylate, AAo: ascending aorta, CRP: C-reactive protein, D to R: descending colon to rectum, IFX: infliximab, Lt. CCA: left common carotid artery, MTX: methotrexate, Others: other immunosuppressive agents, PET: positron emission tomography, pMS: partial Mayo score, TAC: tacrolimus, TCZ: tocilizumab Case 2 A 72-year-old man was admitted for a fever of unknown origin. Bilateral auricular redness and saddle nose were observed. He also suffered from polyarthralgia and swelling, which seemed to be consistent with rheumatoid arthritis. There was no abdominal pain at this time, but diarrhea was observed. Contrast-enhanced CT did not reveal any significant findings other than multiple diverticula in the sigmoid colon. Auricular cartilage biopsy was performed and RP was diagnosed. High dose PSL (1.2 mg/kg) led to an immediate improvement in inflammation, and arthralgia and diarrhea also disappeared. However, it relapsed when the PSL dose was reduced to 8 mg daily. Arthralgia also recurred along with the inflammation. Cyclosporine A therapy was added, but it could not be continued due to renal impairment. Since a previous report described the successful treatment of RP with TCZ (2), and our patient's arthritis also met ACR/EULAR criteria of rheumatoid arthritis (6), TCZ was started. As in the previous case, in our case as well, TCZ was effective in treating the chondritis and arthritis. After four weeks of therapy, however, he developed diarrhea, melena and abdominal pain. Colonoscopy showed diffuse erosions and multiple ulcers from the rectum to sigmoid colon. A mucosal biopsy showed non-specific inflammatory findings consistent with UC. No intranuclear injection bodies were observed on Hematoxylin & Eosin staining, and immunohistochemistry showed no evidence of Cytomegalovirus (CMV)infection (Fig. 3a-d). CMV-DNA was not detected by apolymerase chain reaction testing of biopsy tissue. Stool cultures failed to isolate any significant pathogenic microorganisms, including Clostridium difficile. Glutamate dehydrogenase antigen and toxin A/B of Clostridium difficile in the stool were also undetectable. A diagnosis of UC was made, and high dose PSL with 5-aminosalicylate (4,800 mg daily) therapy was started and TCZ was discontinued. However, ten days after commencing treatment, perforation of the sigmoid colon occurred, and total proctocolectomy was performed. The resected specimen showed typical evidence of pancolitis, and UC was definitively diagnosed (Fig. 3e-h). Figure 3. Findings of colonoscopy and the resected specimen in case 2. a: Colonoscopy findings of the sigmoid colon. b: Microscopic findings, low-power field, Hematoxylin and Eosin (H&E) staining. c: High power field of b. d: Immunohistochemistry study for Cytomegalovirus. Colonoscopy showed diffuse erosions and multiple ulcers from the rectum to sigmoid colon (a). Microscopic findings showed nonspecific inflammation, mainly in the mucosa. There were no nuclear inclusions on H&E staining and no evidence of CMV infection in immunohistochemistry. e: The resected specimen of the whole colon. f: The site of perforation in the sigmoid colon (white arrow). g: Microscopic findings of the colon mucosa, H&E staining, high-power field. h: Microscopic findings at the site of perforation, H&E staining, low-power field. The resected specimen showed perforation of the sigmoid colon and diffuse erosion throughout the entire colon. The residual mucosa showed the findings of pseudopolyps (e, f). Microscopic evaluation showed marked inflammatory cell infiltration and crypt abscesses, consistent with typical UC (g, h). The site of perforation was infiltrated with inflammatory cells in all layers, but it was not possible to determine whether it was consistent with diverticula. Discussion UC is an inflammatory bowel disease of the colonic mucosa that causes multiple erosions and ulcers. Although its etiology remains unclear, it has been suggested to be related to the intestinal microbiome, hereditary factors and malfunction of the immune system. Various indicators are used to measure UC activity, including IL-6. According to previous reports, the IL-6 levels in the serum and colonic mucosa of UC patients increase in association with the disease activity (7,8). Hence, TCZ seems effective in the treatment of UC. However, our cases did not experience any improvement with TCZ. In case 1, UC was improved by changing TCZ to IFX without increasing the dose of steroids and immunosuppressive agents. In case 2 as well, while TCZ was effective for the chondritis, symptoms of UC became apparent and worsened after he started TCZ. Although these results seem to contradict the theory related to the efficacy of TCZ for UC, cases similar to ours have been reported. Atreya et al. reported a case of rheumatoid arthritis with UC that was exacerbated following treatment with TCZ (9). There have also been reports of multiple gastrointestinal ulcer complications other than UC due to TCZ (10,11). As shown in these cases, TCZ appears to induce some kind of intestinal toxicity, which can be explained by the fact that TCZ inhibits one of the non-inflammatory effects of IL-6, namely, intestinal mucosal protection. IL-6 is a pleiotropic cytokine that activates not only the inflammatory response, but also hematopoiesis, angiogenesis and other physiological processes. It is also known to be an important cytokine for tissue regeneration and repair (12). Several reports of murine studies showed that IL-6 signaling plays an essential role in proliferation and maintenance of the intestinal epithelium. According to Jin et al., administration of IL-6 causes intestinal epithelial proliferation that increases intestinal volume and reduces reperfusion injury after ischemia. In contrast, IL-6 deficient mice showed impaired intestinal epithelial repair following damage by 5-fluorouracil (13). Additionally, Tebbutt et al. showed that IL-6 deficient mice had an increased risk of epithelial erosion and mortality compared to wild type mice with dextran sodium sulfate -induced colitis, in a mouse model of UC (14). IL-6 contributes to tissue repair by binding to the IL-6 receptor expressed on cell membranes (mIL-6R) and activating the STAT-3 pathway, via a process called classic signaling. On the other hand, IL-6 also forms a complex with the soluble IL-6 receptor (sIL-6R) that drifts in serum, and induces other signals via glycoprotein 130 (gp130) on the cell membrane, called trans-signaling, which activates the immune system and causes inflammation (15). TCZ exerts anti-inflammatory effects by inhibiting trans-signaling, but since it has a similar affinity for both mIL-6R and sIL-6R, it is expected that intestinal epithelial regeneration is also impaired (16). In our cases, we considered that the mucosal regeneration dysfunction was more problematic than the anti-inflammatory effect of TCZ, leading to a persistence of the mucosal damage and a worsening of inflammation. Previously, the possibility of adverse effects of TCZ on the intestine has been discussed, and TCZ has been known to carry a greater risk for lower gastrointestinal perforation as compared to non-steroidal anti-inflammatory drugs and other biologics (17,18). Patients with diverticula are considered to be particularly at risk because they are inherently prone to diverticulitis, and there is also a warning about this on the medical package insert (19). This is because of the strong anti-inflammatory effect of TCZ, which can exacerbate infection and mask its symptoms, thereby delaying disease detection. Additionally, it has also been hypothesized that the adipose tissue accumulates locally to cover inflamed diverticula, and this response is prevented by inhibiting IL-6 signaling (20-22). In our opinion, in addition to these factors, delayed wound healing due to classic signaling inhibition might be involved in the adverse effects of TCZ on the intestines. UC is generally less likely to cause perforation than other inflammatory bowel diseases, with an estimated incidence of about 3%. Approximately 70% of perforation cases have been reported to be associated with toxic megacolon (23,24), but in our case 2, there was no evidence of toxic megacolon. Since the perforation point was deeply ulcerated, it was unclear histologically or grossly whether the perforation was consistent with diverticula. It is possible that a diverticulum was perforated, as is the known theory, but if not, perforation is a relatively rare complication of UC, as mentioned above. Our experience suggests that TCZ might be associated with a perforation risk in patients with UC. Our cases suggest that TCZ has the potential to cause adverse effects on the intestinal mucosa, and it is therefore considered to be a risk factor for UC with TCZ therapy. Certainly, some cases in which TCZ treatment improved UC, as opposed to our cases and those discussed above, have been reported (25-28). The contradictory results seem to be due to the balance between the disadvantages of inhibiting classic-signaling and the benefits of blocking trans-signaling. However, patient background factors that might improve or exacerbate the disease remain unknown. As in case 2, UC is a disease that must be managed with care, because exacerbations of the disease might require emergency surgery or have serious consequences. Although the effect of TCZ on UC has not been reported in sufficient numbers to be conclusive, it should be used with caution given its potential for causing an exacerbation of the disease. Conclusion TCZ therapy should be administered with care in patients complicated with UC, because it can worsen their intestinal condition. Written informed consent was obtained from both patients for publication of this article. The authors state that they have no Conflict of Interest (COI).	162 mg (milligrams).	DrugDosage	CC BY-NC-ND	33281154	18,645,469	2021-05-15
What was the outcome of reaction 'Colitis ulcerative'?	Exacerbation of Ulcerative Colitis with Tocilizumab: A Report of Two Cases, One with Takayasu Arteritis and the Other with Relapsing Polychondritis. Tocilizumab (TCZ), a biologic that blocks the signal transduction of interleukin-6, has been used for the treatment of various autoimmune diseases. Many of these cases are sometimes complicated by ulcerative colitis (UC). However, the effect of TCZ on UC is unclear. We experienced two cases with concomitant UC that were treated with TCZ, one for Takayasu arteritis (TAK) and the other for relapsing polychondritis (RP). TCZ did not improve UC in either of these cases. TCZ might have adverse effects on the intestinal tract, since interleukin-6 signaling plays an important role in intestinal epithelium maintenance. Treatment with TCZ should therefore be carefully provided in patients complicated with UC. Introduction With the advent of biologics in recent years, the outcomes of autoimmune diseases and inflammatory bowel diseases, such as Takayasu arteritis (TAK), relapsing polychondritis (RP) and ulcerative colitis (UC) have greatly improved. TAK, RP and UC are all inflammatory diseases of unknown etiology, which might involve autoimmune mechanisms. These diseases involve large vessels, cartilage and colorectal mucosa, respectively, as the focus of inflammation, and each can cause serious or fatal complications. Hence, their control is essential. However, there are refractory cases of these conditions, in which remission cannot be induced even with the combination of steroids and immunosuppressive agents. The biologic tocilizumab (TCZ) is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, that exerts strong anti-inflammatory effects by blocking the signaling of IL-6, a typical proinflammatory cytokine. TCZ has become one of the mainstays in the treatment of TAK, because it is expected to reduce steroid dose and induce remission in patients who are refractory to previous treatment (1). In RP as well, the effectiveness of various biologics, including TCZ, has been reported (2). Additionally, the status of biologics in the treatment of UC has been well established prior to their use for TAK and RP (3). Clinically, TAK and UC are often seen in the same patient, as is UC and RP (4,5). Therefore, there might be several opportunities to use TCZ in patients who also have UC. However, since the biologics usually used as the first line therapy for UC include tumor necrosis factor inhibitors, there are only few reports of cases of UC treated with TCZ. Hence, the safety and efficacy of TCZ for UC is currently unknown. We herein report two cases that were treated with TCZ, one for TAK and the other for RP, both of which were complicated with UC, along with a review of the relevant literature. Case Reports Case 1 A 17-year-old woman was admitted to our hospital with fever, diarrhea and melena. The blood pressure in her left arm (74/54 mmHg) was lower than in the right (108/60 mmHg), and computed tomography (CT) showed occlusion of the subclavian artery and thickening of the vascular wall in the aortic arch and the common carotid arteries bilaterally. Additionally, colonoscopy revealed mucosal edema and erosion of the entire colon, leading to a diagnosis of TAK and UC (Fig. 1). Her partial Mayo score (pMS), a simplified UC activity measure, was evaluated as 9 at this time. High dose prednisolone (PSL) therapy (1 mg/kg/day) and 5-aminosalicylate were started, which led to remission and her discharge from the hospital, although the PSL dose could not be reduced to less than 17 mg orally daily due to TAK relapse with steroid reduction, despite combination treatment consisting of steroid therapy with tacrolimus (TAC) and methotrexate (MTX). No diarrhea or hematochezia were observed during this period, the disease activity of UC seemed to have passed at a low level. After about a year and a half, TCZ became available for TAK in Japan. Therefore, on day 502 after her initial visit, we started the intradermal injection of 162 mg TCZ once every two weeks. Since TCZ improved vasculitis, we once again attempted to reduce the steroid dose. However, the UC worsened with reduction of PSL, although TAK activity remained low. Positron emission tomography (PET) showed little fluorodeoxyglucose (FDG) uptake in the main artery, but with a high accumulation from the descending colon to the rectum; the maximum standardized uptake value (SUVmax) was 9.7 on day 800 after her initial visit. Her pMS was 5 at this time. We continued TCZ therapy after adjusting the steroid dose and immunosuppressive agents for 6 months. As a result, the treatment was maintained for about three months as described below: PSL 10 mg daily, TAC 8 mg daily, and MTX 14 mg weekly. The steroid dosage was not increased at this stage because she did not give her consent. Subsequently, a second PET performed on day 947 after her initial presentation showed no satisfactory effect on the UC. Her pMS remained at 5-6, which was interpreted as no clinical improvement. Hence, we discontinued TCZ and switched to infliximab (IFX) 5 mg/kg, which led to an improvement in her gastrointestinal symptoms without any exacerbation of TAK. The FDG uptake by the colon was also reduced. Her pMS decreased to 1. The clinical course of this case is shown below (Fig. 2) IFX was administered at two, four and eight weeks after the first dose, and then every eight weeks thereafter. Figure 1. Findings of enhanced CT, CT-angiography and colonoscopy in case 1. Enhanced CT scan showed vessel wall thickening in bilateral common carotid arteries, and the left subclavian artery was completely occluded, as seen on CT-angiography (a, b). Colonoscopy revealed mucosal edema and erosion of the entire colon, leading to ulcerative colitis (c, d). Figure 2. Clinical course of case 1. TCZ was started on day 502 after the initial visit, and PET-CT was performed on days 800, 947 and 1122. Colonoscopy was also performed about one week before or after each PET-CT scan. TCZ improved vasculitis, but was not effective for colitis. TCZ failed to reduce pMS, and PET-CT showed no reduction in SUVmax of the descending colon to rectum. Conversely, IFX improved both clinical symptoms and SUVmax of the descending colon to rectum, without relapse of TAK. 5-ASA: 5-aminosalicylate, AAo: ascending aorta, CRP: C-reactive protein, D to R: descending colon to rectum, IFX: infliximab, Lt. CCA: left common carotid artery, MTX: methotrexate, Others: other immunosuppressive agents, PET: positron emission tomography, pMS: partial Mayo score, TAC: tacrolimus, TCZ: tocilizumab Case 2 A 72-year-old man was admitted for a fever of unknown origin. Bilateral auricular redness and saddle nose were observed. He also suffered from polyarthralgia and swelling, which seemed to be consistent with rheumatoid arthritis. There was no abdominal pain at this time, but diarrhea was observed. Contrast-enhanced CT did not reveal any significant findings other than multiple diverticula in the sigmoid colon. Auricular cartilage biopsy was performed and RP was diagnosed. High dose PSL (1.2 mg/kg) led to an immediate improvement in inflammation, and arthralgia and diarrhea also disappeared. However, it relapsed when the PSL dose was reduced to 8 mg daily. Arthralgia also recurred along with the inflammation. Cyclosporine A therapy was added, but it could not be continued due to renal impairment. Since a previous report described the successful treatment of RP with TCZ (2), and our patient's arthritis also met ACR/EULAR criteria of rheumatoid arthritis (6), TCZ was started. As in the previous case, in our case as well, TCZ was effective in treating the chondritis and arthritis. After four weeks of therapy, however, he developed diarrhea, melena and abdominal pain. Colonoscopy showed diffuse erosions and multiple ulcers from the rectum to sigmoid colon. A mucosal biopsy showed non-specific inflammatory findings consistent with UC. No intranuclear injection bodies were observed on Hematoxylin & Eosin staining, and immunohistochemistry showed no evidence of Cytomegalovirus (CMV)infection (Fig. 3a-d). CMV-DNA was not detected by apolymerase chain reaction testing of biopsy tissue. Stool cultures failed to isolate any significant pathogenic microorganisms, including Clostridium difficile. Glutamate dehydrogenase antigen and toxin A/B of Clostridium difficile in the stool were also undetectable. A diagnosis of UC was made, and high dose PSL with 5-aminosalicylate (4,800 mg daily) therapy was started and TCZ was discontinued. However, ten days after commencing treatment, perforation of the sigmoid colon occurred, and total proctocolectomy was performed. The resected specimen showed typical evidence of pancolitis, and UC was definitively diagnosed (Fig. 3e-h). Figure 3. Findings of colonoscopy and the resected specimen in case 2. a: Colonoscopy findings of the sigmoid colon. b: Microscopic findings, low-power field, Hematoxylin and Eosin (H&E) staining. c: High power field of b. d: Immunohistochemistry study for Cytomegalovirus. Colonoscopy showed diffuse erosions and multiple ulcers from the rectum to sigmoid colon (a). Microscopic findings showed nonspecific inflammation, mainly in the mucosa. There were no nuclear inclusions on H&E staining and no evidence of CMV infection in immunohistochemistry. e: The resected specimen of the whole colon. f: The site of perforation in the sigmoid colon (white arrow). g: Microscopic findings of the colon mucosa, H&E staining, high-power field. h: Microscopic findings at the site of perforation, H&E staining, low-power field. The resected specimen showed perforation of the sigmoid colon and diffuse erosion throughout the entire colon. The residual mucosa showed the findings of pseudopolyps (e, f). Microscopic evaluation showed marked inflammatory cell infiltration and crypt abscesses, consistent with typical UC (g, h). The site of perforation was infiltrated with inflammatory cells in all layers, but it was not possible to determine whether it was consistent with diverticula. Discussion UC is an inflammatory bowel disease of the colonic mucosa that causes multiple erosions and ulcers. Although its etiology remains unclear, it has been suggested to be related to the intestinal microbiome, hereditary factors and malfunction of the immune system. Various indicators are used to measure UC activity, including IL-6. According to previous reports, the IL-6 levels in the serum and colonic mucosa of UC patients increase in association with the disease activity (7,8). Hence, TCZ seems effective in the treatment of UC. However, our cases did not experience any improvement with TCZ. In case 1, UC was improved by changing TCZ to IFX without increasing the dose of steroids and immunosuppressive agents. In case 2 as well, while TCZ was effective for the chondritis, symptoms of UC became apparent and worsened after he started TCZ. Although these results seem to contradict the theory related to the efficacy of TCZ for UC, cases similar to ours have been reported. Atreya et al. reported a case of rheumatoid arthritis with UC that was exacerbated following treatment with TCZ (9). There have also been reports of multiple gastrointestinal ulcer complications other than UC due to TCZ (10,11). As shown in these cases, TCZ appears to induce some kind of intestinal toxicity, which can be explained by the fact that TCZ inhibits one of the non-inflammatory effects of IL-6, namely, intestinal mucosal protection. IL-6 is a pleiotropic cytokine that activates not only the inflammatory response, but also hematopoiesis, angiogenesis and other physiological processes. It is also known to be an important cytokine for tissue regeneration and repair (12). Several reports of murine studies showed that IL-6 signaling plays an essential role in proliferation and maintenance of the intestinal epithelium. According to Jin et al., administration of IL-6 causes intestinal epithelial proliferation that increases intestinal volume and reduces reperfusion injury after ischemia. In contrast, IL-6 deficient mice showed impaired intestinal epithelial repair following damage by 5-fluorouracil (13). Additionally, Tebbutt et al. showed that IL-6 deficient mice had an increased risk of epithelial erosion and mortality compared to wild type mice with dextran sodium sulfate -induced colitis, in a mouse model of UC (14). IL-6 contributes to tissue repair by binding to the IL-6 receptor expressed on cell membranes (mIL-6R) and activating the STAT-3 pathway, via a process called classic signaling. On the other hand, IL-6 also forms a complex with the soluble IL-6 receptor (sIL-6R) that drifts in serum, and induces other signals via glycoprotein 130 (gp130) on the cell membrane, called trans-signaling, which activates the immune system and causes inflammation (15). TCZ exerts anti-inflammatory effects by inhibiting trans-signaling, but since it has a similar affinity for both mIL-6R and sIL-6R, it is expected that intestinal epithelial regeneration is also impaired (16). In our cases, we considered that the mucosal regeneration dysfunction was more problematic than the anti-inflammatory effect of TCZ, leading to a persistence of the mucosal damage and a worsening of inflammation. Previously, the possibility of adverse effects of TCZ on the intestine has been discussed, and TCZ has been known to carry a greater risk for lower gastrointestinal perforation as compared to non-steroidal anti-inflammatory drugs and other biologics (17,18). Patients with diverticula are considered to be particularly at risk because they are inherently prone to diverticulitis, and there is also a warning about this on the medical package insert (19). This is because of the strong anti-inflammatory effect of TCZ, which can exacerbate infection and mask its symptoms, thereby delaying disease detection. Additionally, it has also been hypothesized that the adipose tissue accumulates locally to cover inflamed diverticula, and this response is prevented by inhibiting IL-6 signaling (20-22). In our opinion, in addition to these factors, delayed wound healing due to classic signaling inhibition might be involved in the adverse effects of TCZ on the intestines. UC is generally less likely to cause perforation than other inflammatory bowel diseases, with an estimated incidence of about 3%. Approximately 70% of perforation cases have been reported to be associated with toxic megacolon (23,24), but in our case 2, there was no evidence of toxic megacolon. Since the perforation point was deeply ulcerated, it was unclear histologically or grossly whether the perforation was consistent with diverticula. It is possible that a diverticulum was perforated, as is the known theory, but if not, perforation is a relatively rare complication of UC, as mentioned above. Our experience suggests that TCZ might be associated with a perforation risk in patients with UC. Our cases suggest that TCZ has the potential to cause adverse effects on the intestinal mucosa, and it is therefore considered to be a risk factor for UC with TCZ therapy. Certainly, some cases in which TCZ treatment improved UC, as opposed to our cases and those discussed above, have been reported (25-28). The contradictory results seem to be due to the balance between the disadvantages of inhibiting classic-signaling and the benefits of blocking trans-signaling. However, patient background factors that might improve or exacerbate the disease remain unknown. As in case 2, UC is a disease that must be managed with care, because exacerbations of the disease might require emergency surgery or have serious consequences. Although the effect of TCZ on UC has not been reported in sufficient numbers to be conclusive, it should be used with caution given its potential for causing an exacerbation of the disease. Conclusion TCZ therapy should be administered with care in patients complicated with UC, because it can worsen their intestinal condition. Written informed consent was obtained from both patients for publication of this article. The authors state that they have no Conflict of Interest (COI).	Recovering	ReactionOutcome	CC BY-NC-ND	33281154	18,645,469	2021-05-15
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Femur fracture'.	Precontoured Plate Fixation for Incomplete Atypical Diaphyseal Fracture of Femur using Three-Dimensional Printing Rapid Prototyping: Two Cases Reports. BACKGROUND Reconstruction intramedullary nail spanning the whole length of the femur has been the gold standard treatment for complete atypical diaphyseal fractures of the femur (ADF). However, in cases of incomplete ADF combined with severe bowing, this approach might have complications and lead to iatrogenic complete fracture. We report two cases of incomplete ADF with severe bowing using a precontoured plate (PCP) after rapid prototyping (RP) of the deformed femurs with three-dimensional printing (3DP) technology. METHODS Two patients presented with gradually worsening thigh pain, especially during walking. The patients had been using bisphosphonates for 4 and 10 years, respectively. Radiography showed an incomplete fracture in the lateral cortex of the right femur shaft. The lateral bowing angles measured in the affected femurs were 15° and 14°, and the anterior bowing angles were 20° and 16°, respectively. In bone scans, both patients showed hot uptake in the right mid-shaft of the femur. Preoperatively, the affected femur of the patient was reconstructed by 3DP RP using CT, and the plate was bent to the shape of the bone model. The ADF was fixed with a PCP using the minimally invasive plate osteosynthesis technique. Both patients were encouraged to start full weight-bearing and return to their preinjury activity level in daily life immediately after surgery. At 2 years postoperatively, radiography showed healing of the fracture site without recurrence of thigh pain and implant-related problems. CONCLUSIONS Although intramedullary nailing is the standard surgical treatment for complete ADF, PCP using 3DP RP could be an effective treatment option for incomplete ADF with severely curved femur. Introduction For complete atypical diaphyseal fractures of the femur (ADF), reconstruction intramedullary nailing (IMN) panning the whole length of the femur has been considered the standard surgical treatment 1 , 2 . However, in cases of incomplete ADF combined with severe bowing, this procedure might result in complications and lead to iatrogenic complete fracture, resulting in delayed union or non‐union 3 , 4 . Plating has been proposed as an alternative 5 , 6 but may have disadvantages, such as the potential risk of developing neck fractures, the considerable time necessary to modify the plate into a form that fits perfectly to the bowed femur during the operation, and the insufficient length to cover the whole femur due to the complexity of the three‐dimensional (3D) deformity 7 . We report two cases of incomplete ADF with markedly curved femurs using a pre‐contoured plate (PCP) after rapid‐prototyping (RP) the deformed femurs with three‐dimensional printing (3DP) technology. Case Reports Patient 1 A 75‐year‐old woman presented to our clinic with a 3‐month history of right thigh pain. She was able to walk independently outdoors before symptom onset. The patient had no history of recent trauma, and thigh pain was aggravated during walking, especially in the stance phase. However, she had no pain in other sites. The patient had used ibandronate 4 years previously due to osteoporosis. The patient had undergone internal fixation with proximal femur nail for intertrochanteric fracture of the left femur 11 years previously in another institution and internal fixation for left distal radius fracture 6 years previously in our institution. The patient complained of limb‐length discrepancy due to a shorter left leg after the previous surgery on the left femur. Besides osteoporosis, the patient had never been diagnosed with any disease affecting the bone metabolism, such as osteogenesis imperfecta. On physical examination, there was mild tenderness in the right mid‐thigh. There was no clinical sign of infection, such as erythema, and local heat was not observed. The results of routine laboratory tests, including serum C‐reactive protein level and erythrocyte sedimentation rate, were within normal limits. Plain radiography showed transverse radiolucent fracture line on the apex of the lateral cortex of the right mid‐shaft of the femur (Fig. 1), but the contralateral side of the femur was intact. According to Sasaki et al. 8 , the lateral bowing angle was 14° and the anterior bowing angle was 16°. Bone single photon emission computed tomography (SPECT) showed hot uptake in the right femoral shaft (Fig. 2). The bone mineral density (BMD) of the lumbar spine (L1–4, 0.639 g/cm2; T‐score: −3.9) and the proximal femur (0.607 g/cm2; T‐score, −2.7) was evaluated by dual‐energy X‐ray absorptiometry (DEXA). Fig. 1 Radiographs of patient 1. Plain radiographs showed transverse radiolucent line on the apex of the lateral cortex of the right mid‐shaft of the femur. Fig. 2 Bone single photon emission CT of patient 1. (A) Preoperative nuclear medical images showed hot uptake in the right femoral shaft (arrowhead). (B) Two years after surgery, no or minimal uptake of the right femoral mid‐shaft was observed (arrowhead). The patient was advised to discontinue ibandronate use and start teriparatide injection 2 , 9 . According to the scoring system for identifying impending complete fractures in incomplete atypical femoral fractures (AFF) 10 , the patient scored a total of 9 points, an indication for prophylactic surgery: 2 for diaphyseal lesion, 3 for functional pain, 3 for intact on the contralateral side, and 1 point for a focal radiolucent line. Due to severe bowing of the affected femur, we planned to perform prophylactic PCP spanning the whole length of the bowed femur. CT was performed on the patient's right femur, and a bone model was reconstructed using KM3D version 1.0 (Kyungpook National University, Institute of Advanced Convergence Technology, Daegu, Korea). A locking compression plate (DePuySynthes, Oberdorf, Switzerland) was precontoured preoperatively according to the shape of the bone model (Fig. 3). The bone model was sterilized for intraoperative use and placed on the same position to that of the femur under C‐arm guidance to enhance the accurate position of the PCP (Fig. 4A). Taking into consideration the 3D bending of the plate, an anterolateral skin incision, instead of a lateral incision, for plate entry was made, and submuscular insertion of PCP was performed using the routine minimally invasive plate osteosynthesis (MIPO) technique (Fig. 4B). To reduce the potential risk of femoral neck fracture due to stress concentration, one 80‐mm locking screw was inserted through the screw hole in the plate and two additional cannulated screws were inserted using the same incision at the entry site (Fig. 4C). The patient was encouraged to start full weight bearing and return to the pre‐injured activity level of daily life immediately after surgery. Fig. 3 Precontoured plate for patient 1. The locking compression plate was precontoured according to the shape of the bone model. Because of the three‐dimensional complex deformity of the severely bowed femur, the proximal part of the precontoured plate was placed on the anterolateral aspect of the proximal femur. (A) Anteroposterior view. (B) Lateral view. Fig. 4 Surgical process of patient 1. (A) Before making the incision, the sterilized bone model was placed on the same position to that of the femur under C‐arm guidance to enhance the accurate position of the PCP and reduce the operative time. (B) After submuscular insertion of PCP, we confirmed the correct position of the plate matching the bowed femur using both fluoroscopic guidance and preoperative images (shown in Fig. 3 using a smartphone). (C) Immediate postoperative radiography demonstrated the accurate position of the PCP, similar to the preoperative planning shown in Fig. 3, with additional screws toward the right femoral neck. Thigh pain subsided 6 weeks postoperatively, and the patient returned to complete daily life. Radiography performed 2 years postoperatively showed bone union and no progression of femoral bowing or implant‐related problems (Fig. 5). Fig. 5 Radiographs of patient 1 at last follow up. Radiographs taken at 2 years postoperatively showed bone union and no progression of femoral bowing or implant‐related problems. Patient 2 A 78‐year‐old woman visited our orthopaedic department due to right thigh pain for 6 months. Thigh pain developed insidiously and gradually worsened. She had been unable to walk independently for 1 week. The patient had no history of recent trauma. No pain was noted in other sites. The patient had been using alendronate for treatment of osteoporosis for 10 years. The patient underwent total knee arthroplasty on both knees 10 years previously. She was diagnosed with an intertrochanteric fracture of the left femur and fracture of the symphysis pubis 4 years previously after slipdown. For intertrochanteric fractures, internal fixation with proximal femoral nail has been performed in another institution. She complained that the left lower limb was shortened after the previous surgery. Besides osteoporosis, she had never been diagnosed with any disease that might affect the bones. On physical examination, there was moderate tenderness in the right thigh. There was no clinical sign of infection. Results of routine laboratory tests revealed no specific abnormality. Radiographs showed transverse radiolucent line in the lateral cortex of the mid‐shaft of the femur (Fig. 6), but there was no abnormality on the contralateral side of the femur. The curvature of the femur was marked, the lateral bowing angle was 15°, and the anterior bowing angle was 20°. Bone SPECT showed hot uptake in the right femoral shaft and symphysis pubis (Fig. 7). On DEXA, BMD of the lumbar spine (L2‐4, 0.718 g/cm2, T‐score: ‐2.7) and proximal femur (0.413 g/cm2, T‐score: ‐3.8) was obtained. Fig. 6 Radiographs of patient 2. Plain radiographs showed transverse radiolucent line in the lateral cortex of the mid‐shaft of the femur. Fig. 7 Bone single photon emission CT of patient 2. (A) Preoperative nuclear medical images showed hot uptake in the mid‐shaft of the right femur shaft and around the symphysis pubis (arrowhead). (B) Sixteen months after surgery, uptake in the mid‐shaft of the right femur was decreased, but hot uptake was still observed around the symphysis pubis (arrowhead). The patient was advised to discontinue alendronate use and start teriparatide injection. Based on the scoring system to evaluate impending complete fractures, the patient scored 9 points, which was an indication for prophylactic surgery. Because the curvature of the affected femur was marked, we planned prophylactic surgery using PC‐WBP. We performed CT to obtain the morphologic features of the affected femur, and the bone model was reconstructed using 3DP RP. A locking compression plate (DePuySynthes, Oberdorf, Switzerland) was molded preoperatively according to the shape of the bone model (Fig. 8). The bone model was sterilized and used intraoperatively to assist the MIPO technique (Fig. 9A). Three additional cannulated screws were fixed using the same incision at the entry site to decrease the potential risk of femoral neck fracture (Fig. 9B). The patient was encouraged to start full weight‐bearing and return to their preinjury activity level in daily life immediately after surgery. Fig. 8 Precontoured plate for patient 2. The locking compression plate was prebent to match the shape of the reconstructed bone model preoperatively. Because the curvature of the femur was more severe than that in patient 1, the proximal part of the precontoured plate was placed on the more anterior aspect of the proximal femur. (A) Anterioposterior view. (B) Lateral view. Fig. 9 Surgical process of patient 2. (A) Bone model was sterilized and used intraoperatively to assist minimally invasive plate osteosynthesis (MIPO) technique. (B) Immediate postoperative plain X‐rays of the right femur. The patient did not report pain in the right thigh and returned to complete daily life at the last follow‐up. Radiography performed at 16 months postoperatively showed ongoing union and no progression of femoral bowing or implant‐related problems (Fig. 10). Fig. 10 Radiographs of patient 2 at last follow‐up. Radiography performed 16 months postoperatively showed and no progression of femoral bowing or implant‐related problems. Discussion We diagnosed incomplete ADF through physical examination and radiologic evaluation in two patients complaining of mid‐thigh pain and confirmed the indication for prophylactic surgery with a scoring system. Both patients had severely bowed femurs, and the bone model was reconstructed with 3DP RP. A locking compression plate spanning the whole femur was contoured preoperatively according to the shape of the bone model and then fixed to the bone using the MIPO technique. At 18 months postoperatively, we observed bone union, no progression of bowing, and no implant‐related problems on radiography. Furthermore, the patients did not complain of pain and were able to return to their preinjury daily lives. The treatment choice for incomplete ADF depends on the patient's symptoms and radiological findings. If there is no pain, conservative treatment can be attempted initially for an incomplete ADF without a radiolucent fracture line 1 . Recently, Min et al. (2017) developed a scoring system to determine the necessity of prophylactic surgery for incomplete ADF 10 . Both cases in the present study corresponded to the indication for surgery. Prophylactic surgery foe incomplete ADF, if indicated, has been reported to reduce pain and prevent progression to complete fracture 1 . Moreover, compared to the surgery for complete ADF, prophylactic fixation for incomplete ADF has advantages, such as shorter time for union, shorter hospital stay and fewer complications 2 . Reconstruction IMN has been considered as a standard method of prophylactic fixation for incomplete subtrochanteric AFF due to its better load‐sharing capacity and less bending moment 1 , 2 . However, prophylactic nailing for incomplete ADF, which is usually combined with a bowed femur, remains a challenge. Various methods for ADF have been proposed to overcome the significant anterolateral bowing of the femur, including far lateral entry point, use of the contralateral side of the nail, and external rotation of the nail 3 . However, in cases combined with severe anterolateral bowing, IMN may cause iatrogenic progression to complete fracture, which may lead to delayed union or non‐union 1 , 2 . Moreover, if femoral bowing occurs bilaterally, which is common in patients with ADF, IMN with iatrogenic or intentional complete fractures may straighten the curved femur and make the affected side longer than the contralateral side, leading to limb length discrepancy (LLD). Because both patients in our report complained of LLD due to a shortened contralateral lower limb after previous fixation for an intertrochanteric fracture, there was a potential risk of worsening LLD when complete fracture occurred during IMN. Biomechanically, tensile loading is concentrated in the lateral cortex of the curved femur in daily life, such as walking, and ADF occur in the region where maximal tensile loading is applied 2 . By placing the plate on the lateral side, the tensile force is reduced to prevent crack propagation, and the strain that prohibits bone formation is reduced to promote the healing process 6 . It can also prevent the progression to complete fracture that may occur during nail insertion and maintain lower limb length. Biologically, a previous study reported that lateral plate fixation had advantages over nailing in terms of less intramedullary damage and faster bone union in incomplete ADF 5 . Nevertheless, long‐term follow up might be necessary to identify further progression of deformity and subsequent hardware failure. Recently, some case reports using plates in an incomplete ADF demonstrated good clinical and radiological results 5 , 6 . Nevertheless, we are concerned about peri‐implant fractures due to stress concentration around the proximal or distal end of the plate by introducing a plate with insufficient length to span the whole length of the femur, as in previous case series. Our speculation for the use of a short plate in previous studies was that, although it was difficult to perform IMN in a severely bowed femur, it was also difficult and required time to contour the longer plate spanning the whole length of the femur during surgery due to the three‐dimensional complex structure of the deformed femur. Moreover, conventional open or mini‐open plating might require extensive incision for placement of the long plate. Thus, we precontoured the plate preoperatively using 3DP RP, and the reconstructed bone model was able to facilitate MIPO during surgery to reduce the operative time. In addition, prophylactic screw fixation toward the femoral neck was performed through the same incision as for plate entry to prevent potential femoral neck fractures due to stress concentration around the tip of the plate. As well as plate fixation in situ according the shape of 3DP RP, we can use this for planning and simulating corrective osteotomy and then fix the osteotomy site with IMN, which might be more sound from a biomechanical point of view. However, this corrective osteotomy may lead to delayed union, non‐union, and limb lengthening. Moreover, both patients had undergone internal fixation for intertrochanteric fractures and had subsequent limb shortening on the contralateral side. Thus, simple valgus osteotomy may aggravate the limb length discrepancy. Even combined shortening osteotomy still has risks for nonunion, delayed union, longer operation time, and more bleeding in patients who are 75 and 78 years of age. Because reduced bone turnover rate and decreased potential for direct bone healing have been reported as characteristics of bisphosphonate‐related ADF 1 , we believe that PCP fixation using MIPO technique could preserve periosteal bone blood supply and subsequent indirect bone healing, similar to that in IMN. Conclusion Although IMN is the standard surgical treatment for ADF, we obtained satisfactory results after use of PCP with 3DP RP in incomplete ADF with severe bowing. Based on our experience, PCP fixation using 3DP RP could be an effective treatment option for incomplete ADF with severe bowing.	IBANDRONIC ACID	DrugsGivenReaction	CC BY-NC-ND	33283486	19,095,549	2021-02
What was the outcome of reaction 'Femur fracture'?	Precontoured Plate Fixation for Incomplete Atypical Diaphyseal Fracture of Femur using Three-Dimensional Printing Rapid Prototyping: Two Cases Reports. BACKGROUND Reconstruction intramedullary nail spanning the whole length of the femur has been the gold standard treatment for complete atypical diaphyseal fractures of the femur (ADF). However, in cases of incomplete ADF combined with severe bowing, this approach might have complications and lead to iatrogenic complete fracture. We report two cases of incomplete ADF with severe bowing using a precontoured plate (PCP) after rapid prototyping (RP) of the deformed femurs with three-dimensional printing (3DP) technology. METHODS Two patients presented with gradually worsening thigh pain, especially during walking. The patients had been using bisphosphonates for 4 and 10 years, respectively. Radiography showed an incomplete fracture in the lateral cortex of the right femur shaft. The lateral bowing angles measured in the affected femurs were 15° and 14°, and the anterior bowing angles were 20° and 16°, respectively. In bone scans, both patients showed hot uptake in the right mid-shaft of the femur. Preoperatively, the affected femur of the patient was reconstructed by 3DP RP using CT, and the plate was bent to the shape of the bone model. The ADF was fixed with a PCP using the minimally invasive plate osteosynthesis technique. Both patients were encouraged to start full weight-bearing and return to their preinjury activity level in daily life immediately after surgery. At 2 years postoperatively, radiography showed healing of the fracture site without recurrence of thigh pain and implant-related problems. CONCLUSIONS Although intramedullary nailing is the standard surgical treatment for complete ADF, PCP using 3DP RP could be an effective treatment option for incomplete ADF with severely curved femur. Introduction For complete atypical diaphyseal fractures of the femur (ADF), reconstruction intramedullary nailing (IMN) panning the whole length of the femur has been considered the standard surgical treatment 1 , 2 . However, in cases of incomplete ADF combined with severe bowing, this procedure might result in complications and lead to iatrogenic complete fracture, resulting in delayed union or non‐union 3 , 4 . Plating has been proposed as an alternative 5 , 6 but may have disadvantages, such as the potential risk of developing neck fractures, the considerable time necessary to modify the plate into a form that fits perfectly to the bowed femur during the operation, and the insufficient length to cover the whole femur due to the complexity of the three‐dimensional (3D) deformity 7 . We report two cases of incomplete ADF with markedly curved femurs using a pre‐contoured plate (PCP) after rapid‐prototyping (RP) the deformed femurs with three‐dimensional printing (3DP) technology. Case Reports Patient 1 A 75‐year‐old woman presented to our clinic with a 3‐month history of right thigh pain. She was able to walk independently outdoors before symptom onset. The patient had no history of recent trauma, and thigh pain was aggravated during walking, especially in the stance phase. However, she had no pain in other sites. The patient had used ibandronate 4 years previously due to osteoporosis. The patient had undergone internal fixation with proximal femur nail for intertrochanteric fracture of the left femur 11 years previously in another institution and internal fixation for left distal radius fracture 6 years previously in our institution. The patient complained of limb‐length discrepancy due to a shorter left leg after the previous surgery on the left femur. Besides osteoporosis, the patient had never been diagnosed with any disease affecting the bone metabolism, such as osteogenesis imperfecta. On physical examination, there was mild tenderness in the right mid‐thigh. There was no clinical sign of infection, such as erythema, and local heat was not observed. The results of routine laboratory tests, including serum C‐reactive protein level and erythrocyte sedimentation rate, were within normal limits. Plain radiography showed transverse radiolucent fracture line on the apex of the lateral cortex of the right mid‐shaft of the femur (Fig. 1), but the contralateral side of the femur was intact. According to Sasaki et al. 8 , the lateral bowing angle was 14° and the anterior bowing angle was 16°. Bone single photon emission computed tomography (SPECT) showed hot uptake in the right femoral shaft (Fig. 2). The bone mineral density (BMD) of the lumbar spine (L1–4, 0.639 g/cm2; T‐score: −3.9) and the proximal femur (0.607 g/cm2; T‐score, −2.7) was evaluated by dual‐energy X‐ray absorptiometry (DEXA). Fig. 1 Radiographs of patient 1. Plain radiographs showed transverse radiolucent line on the apex of the lateral cortex of the right mid‐shaft of the femur. Fig. 2 Bone single photon emission CT of patient 1. (A) Preoperative nuclear medical images showed hot uptake in the right femoral shaft (arrowhead). (B) Two years after surgery, no or minimal uptake of the right femoral mid‐shaft was observed (arrowhead). The patient was advised to discontinue ibandronate use and start teriparatide injection 2 , 9 . According to the scoring system for identifying impending complete fractures in incomplete atypical femoral fractures (AFF) 10 , the patient scored a total of 9 points, an indication for prophylactic surgery: 2 for diaphyseal lesion, 3 for functional pain, 3 for intact on the contralateral side, and 1 point for a focal radiolucent line. Due to severe bowing of the affected femur, we planned to perform prophylactic PCP spanning the whole length of the bowed femur. CT was performed on the patient's right femur, and a bone model was reconstructed using KM3D version 1.0 (Kyungpook National University, Institute of Advanced Convergence Technology, Daegu, Korea). A locking compression plate (DePuySynthes, Oberdorf, Switzerland) was precontoured preoperatively according to the shape of the bone model (Fig. 3). The bone model was sterilized for intraoperative use and placed on the same position to that of the femur under C‐arm guidance to enhance the accurate position of the PCP (Fig. 4A). Taking into consideration the 3D bending of the plate, an anterolateral skin incision, instead of a lateral incision, for plate entry was made, and submuscular insertion of PCP was performed using the routine minimally invasive plate osteosynthesis (MIPO) technique (Fig. 4B). To reduce the potential risk of femoral neck fracture due to stress concentration, one 80‐mm locking screw was inserted through the screw hole in the plate and two additional cannulated screws were inserted using the same incision at the entry site (Fig. 4C). The patient was encouraged to start full weight bearing and return to the pre‐injured activity level of daily life immediately after surgery. Fig. 3 Precontoured plate for patient 1. The locking compression plate was precontoured according to the shape of the bone model. Because of the three‐dimensional complex deformity of the severely bowed femur, the proximal part of the precontoured plate was placed on the anterolateral aspect of the proximal femur. (A) Anteroposterior view. (B) Lateral view. Fig. 4 Surgical process of patient 1. (A) Before making the incision, the sterilized bone model was placed on the same position to that of the femur under C‐arm guidance to enhance the accurate position of the PCP and reduce the operative time. (B) After submuscular insertion of PCP, we confirmed the correct position of the plate matching the bowed femur using both fluoroscopic guidance and preoperative images (shown in Fig. 3 using a smartphone). (C) Immediate postoperative radiography demonstrated the accurate position of the PCP, similar to the preoperative planning shown in Fig. 3, with additional screws toward the right femoral neck. Thigh pain subsided 6 weeks postoperatively, and the patient returned to complete daily life. Radiography performed 2 years postoperatively showed bone union and no progression of femoral bowing or implant‐related problems (Fig. 5). Fig. 5 Radiographs of patient 1 at last follow up. Radiographs taken at 2 years postoperatively showed bone union and no progression of femoral bowing or implant‐related problems. Patient 2 A 78‐year‐old woman visited our orthopaedic department due to right thigh pain for 6 months. Thigh pain developed insidiously and gradually worsened. She had been unable to walk independently for 1 week. The patient had no history of recent trauma. No pain was noted in other sites. The patient had been using alendronate for treatment of osteoporosis for 10 years. The patient underwent total knee arthroplasty on both knees 10 years previously. She was diagnosed with an intertrochanteric fracture of the left femur and fracture of the symphysis pubis 4 years previously after slipdown. For intertrochanteric fractures, internal fixation with proximal femoral nail has been performed in another institution. She complained that the left lower limb was shortened after the previous surgery. Besides osteoporosis, she had never been diagnosed with any disease that might affect the bones. On physical examination, there was moderate tenderness in the right thigh. There was no clinical sign of infection. Results of routine laboratory tests revealed no specific abnormality. Radiographs showed transverse radiolucent line in the lateral cortex of the mid‐shaft of the femur (Fig. 6), but there was no abnormality on the contralateral side of the femur. The curvature of the femur was marked, the lateral bowing angle was 15°, and the anterior bowing angle was 20°. Bone SPECT showed hot uptake in the right femoral shaft and symphysis pubis (Fig. 7). On DEXA, BMD of the lumbar spine (L2‐4, 0.718 g/cm2, T‐score: ‐2.7) and proximal femur (0.413 g/cm2, T‐score: ‐3.8) was obtained. Fig. 6 Radiographs of patient 2. Plain radiographs showed transverse radiolucent line in the lateral cortex of the mid‐shaft of the femur. Fig. 7 Bone single photon emission CT of patient 2. (A) Preoperative nuclear medical images showed hot uptake in the mid‐shaft of the right femur shaft and around the symphysis pubis (arrowhead). (B) Sixteen months after surgery, uptake in the mid‐shaft of the right femur was decreased, but hot uptake was still observed around the symphysis pubis (arrowhead). The patient was advised to discontinue alendronate use and start teriparatide injection. Based on the scoring system to evaluate impending complete fractures, the patient scored 9 points, which was an indication for prophylactic surgery. Because the curvature of the affected femur was marked, we planned prophylactic surgery using PC‐WBP. We performed CT to obtain the morphologic features of the affected femur, and the bone model was reconstructed using 3DP RP. A locking compression plate (DePuySynthes, Oberdorf, Switzerland) was molded preoperatively according to the shape of the bone model (Fig. 8). The bone model was sterilized and used intraoperatively to assist the MIPO technique (Fig. 9A). Three additional cannulated screws were fixed using the same incision at the entry site to decrease the potential risk of femoral neck fracture (Fig. 9B). The patient was encouraged to start full weight‐bearing and return to their preinjury activity level in daily life immediately after surgery. Fig. 8 Precontoured plate for patient 2. The locking compression plate was prebent to match the shape of the reconstructed bone model preoperatively. Because the curvature of the femur was more severe than that in patient 1, the proximal part of the precontoured plate was placed on the more anterior aspect of the proximal femur. (A) Anterioposterior view. (B) Lateral view. Fig. 9 Surgical process of patient 2. (A) Bone model was sterilized and used intraoperatively to assist minimally invasive plate osteosynthesis (MIPO) technique. (B) Immediate postoperative plain X‐rays of the right femur. The patient did not report pain in the right thigh and returned to complete daily life at the last follow‐up. Radiography performed at 16 months postoperatively showed ongoing union and no progression of femoral bowing or implant‐related problems (Fig. 10). Fig. 10 Radiographs of patient 2 at last follow‐up. Radiography performed 16 months postoperatively showed and no progression of femoral bowing or implant‐related problems. Discussion We diagnosed incomplete ADF through physical examination and radiologic evaluation in two patients complaining of mid‐thigh pain and confirmed the indication for prophylactic surgery with a scoring system. Both patients had severely bowed femurs, and the bone model was reconstructed with 3DP RP. A locking compression plate spanning the whole femur was contoured preoperatively according to the shape of the bone model and then fixed to the bone using the MIPO technique. At 18 months postoperatively, we observed bone union, no progression of bowing, and no implant‐related problems on radiography. Furthermore, the patients did not complain of pain and were able to return to their preinjury daily lives. The treatment choice for incomplete ADF depends on the patient's symptoms and radiological findings. If there is no pain, conservative treatment can be attempted initially for an incomplete ADF without a radiolucent fracture line 1 . Recently, Min et al. (2017) developed a scoring system to determine the necessity of prophylactic surgery for incomplete ADF 10 . Both cases in the present study corresponded to the indication for surgery. Prophylactic surgery foe incomplete ADF, if indicated, has been reported to reduce pain and prevent progression to complete fracture 1 . Moreover, compared to the surgery for complete ADF, prophylactic fixation for incomplete ADF has advantages, such as shorter time for union, shorter hospital stay and fewer complications 2 . Reconstruction IMN has been considered as a standard method of prophylactic fixation for incomplete subtrochanteric AFF due to its better load‐sharing capacity and less bending moment 1 , 2 . However, prophylactic nailing for incomplete ADF, which is usually combined with a bowed femur, remains a challenge. Various methods for ADF have been proposed to overcome the significant anterolateral bowing of the femur, including far lateral entry point, use of the contralateral side of the nail, and external rotation of the nail 3 . However, in cases combined with severe anterolateral bowing, IMN may cause iatrogenic progression to complete fracture, which may lead to delayed union or non‐union 1 , 2 . Moreover, if femoral bowing occurs bilaterally, which is common in patients with ADF, IMN with iatrogenic or intentional complete fractures may straighten the curved femur and make the affected side longer than the contralateral side, leading to limb length discrepancy (LLD). Because both patients in our report complained of LLD due to a shortened contralateral lower limb after previous fixation for an intertrochanteric fracture, there was a potential risk of worsening LLD when complete fracture occurred during IMN. Biomechanically, tensile loading is concentrated in the lateral cortex of the curved femur in daily life, such as walking, and ADF occur in the region where maximal tensile loading is applied 2 . By placing the plate on the lateral side, the tensile force is reduced to prevent crack propagation, and the strain that prohibits bone formation is reduced to promote the healing process 6 . It can also prevent the progression to complete fracture that may occur during nail insertion and maintain lower limb length. Biologically, a previous study reported that lateral plate fixation had advantages over nailing in terms of less intramedullary damage and faster bone union in incomplete ADF 5 . Nevertheless, long‐term follow up might be necessary to identify further progression of deformity and subsequent hardware failure. Recently, some case reports using plates in an incomplete ADF demonstrated good clinical and radiological results 5 , 6 . Nevertheless, we are concerned about peri‐implant fractures due to stress concentration around the proximal or distal end of the plate by introducing a plate with insufficient length to span the whole length of the femur, as in previous case series. Our speculation for the use of a short plate in previous studies was that, although it was difficult to perform IMN in a severely bowed femur, it was also difficult and required time to contour the longer plate spanning the whole length of the femur during surgery due to the three‐dimensional complex structure of the deformed femur. Moreover, conventional open or mini‐open plating might require extensive incision for placement of the long plate. Thus, we precontoured the plate preoperatively using 3DP RP, and the reconstructed bone model was able to facilitate MIPO during surgery to reduce the operative time. In addition, prophylactic screw fixation toward the femoral neck was performed through the same incision as for plate entry to prevent potential femoral neck fractures due to stress concentration around the tip of the plate. As well as plate fixation in situ according the shape of 3DP RP, we can use this for planning and simulating corrective osteotomy and then fix the osteotomy site with IMN, which might be more sound from a biomechanical point of view. However, this corrective osteotomy may lead to delayed union, non‐union, and limb lengthening. Moreover, both patients had undergone internal fixation for intertrochanteric fractures and had subsequent limb shortening on the contralateral side. Thus, simple valgus osteotomy may aggravate the limb length discrepancy. Even combined shortening osteotomy still has risks for nonunion, delayed union, longer operation time, and more bleeding in patients who are 75 and 78 years of age. Because reduced bone turnover rate and decreased potential for direct bone healing have been reported as characteristics of bisphosphonate‐related ADF 1 , we believe that PCP fixation using MIPO technique could preserve periosteal bone blood supply and subsequent indirect bone healing, similar to that in IMN. Conclusion Although IMN is the standard surgical treatment for ADF, we obtained satisfactory results after use of PCP with 3DP RP in incomplete ADF with severe bowing. Based on our experience, PCP fixation using 3DP RP could be an effective treatment option for incomplete ADF with severe bowing.	Recovering	ReactionOutcome	CC BY-NC-ND	33283486	19,095,549	2021-02
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'.	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	CISPLATIN, DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, METHOTREXATE, PACLITAXEL, VINBLASTINE	DrugsGivenReaction	CC BY-NC	33285049	20,373,268	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'.	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	CISPLATIN, DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, METHOTREXATE, PACLITAXEL, VINBLASTINE	DrugsGivenReaction	CC BY-NC	33285049	20,373,268	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'.	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	BLEOMYCIN SULFATE, CISPLATIN, CYCLOPHOSPHAMIDE, DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, PACLITAXEL	DrugsGivenReaction	CC BY-NC	33285049	20,373,510	2021-07
What was the dosage of drug 'BLEOMYCIN SULFATE'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	3 CYCLES	DrugDosageText	CC BY-NC	33285049	20,373,510	2021-07
What was the dosage of drug 'CYCLOPHOSPHAMIDE'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	2 CYCLES	DrugDosageText	CC BY-NC	33285049	20,373,510	2021-07
What was the dosage of drug 'DOXORUBICIN'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	2 CYCLES	DrugDosageText	CC BY-NC	33285049	20,373,510	2021-07
What was the dosage of drug 'IFOSFAMIDE'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	3 CYCLES	DrugDosageText	CC BY-NC	33285049	20,373,510	2021-07
What was the dosage of drug 'PACLITAXEL'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	3 CYCLES	DrugDosageText	CC BY-NC	33285049	20,373,510	2021-07
What was the outcome of reaction 'Disease progression'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	Fatal	ReactionOutcome	CC BY-NC	33285049	20,373,268	2021-07
What was the outcome of reaction 'Drug resistance'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	Fatal	ReactionOutcome	CC BY-NC	33285049	20,373,274	2021-07
What was the outcome of reaction 'Respiratory failure'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	Fatal	ReactionOutcome	CC BY-NC	33285049	20,373,268	2021-07
What was the outcome of reaction 'Treatment failure'?	Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center. OBJECTIVE The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. METHODS We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. RESULTS The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy. CONCLUSIONS It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients. Introduction Testicular germ cell tumors (TGCTs) are the most common solid tumors in young men between the ages of 20 and 34 [1]. Although TGCTs most commonly arise in the testicles, occasionally they develop in extragonadal sites without the presence of a primary tumor in the testicles. Extragonadal TGCTs mainly develop in midline locations of the body, such as the anterior mediastinum, retroperitoneum, and pineal gland [2]. TGCTs are divided into two major histological types: pure classic seminoma and non-seminomatous germ cell tumors (NSGCTs) [3]. NSGCTs can be of four subtypes, embryonal carcinoma, yolk sac tumor, teratoma, and choriocarcinoma, and can present a mix of seminomatous and nonseminomatous components. Seminoma often demonstrates indolent behavior, while NSGCTs tend to occur at a younger age and confer higher mortality. Choriocarcinoma is a rare cancer composed of cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblast cells [4]. In embryology, these trophoblast cells are known to contribute to the implantation and subsequent placental development and secrete human chorionic gonadotropin (hCG) to promote the maintenance of the corpus luteum. Therefore, hCG is used as a tumor marker of choriocarcinoma. Choriocarcinoma is classified as gestational or nongestational [5]. Gestational choriocarcinoma refers to choriocarcinoma originating from the trophoblast of any type of gestational event, such as hydatidiform mole, spontaneous abortion, and normal pregnancy. Nongestational choriocarcinoma refers to choriocarcinoma that does not arise from a pregnancy event [6]. Nongestational choriocarcinoma, also called primary choriocarcinoma (PCC), can occur in men, but it is extremely rare [7]. In men, choriocarcinoma is the subtype of NSGCTs with the worst prognosis that presents with high levels of hCG, often widespread metastatic disease, and rapid progression of disease [8]. Moreover, some high-risk patients with very advanced choriocarcinoma develop choriocarcinoma syndrome, which is associated with hemorrhage from the metastatic sites, especially lungs, and has very high mortality rates [4]. To date, the mechanism of male PCC development is not well understood, but the following three hypotheses have been suggested [7]: (1) PCC may arise from retained primordial germ cells that migrate abnormally during embryogenesis; (2) PCC may be a testicular choriocarcinoma metastasis that regressed spontaneously or not; and (3) PCC may initially develop as a nontrophoblastic neoplasm and then transform into a choriocarcinoma. Male PCC is extremely rare, and only few case reports have been published. The clinical features and prognostic factors of male PCC are not well known. Recently, Jiang et al. [7] analyzed data from 113 male patients with PCC and described their clinicopathological features. In this retrospective study, we describe and analyze the clinicopathological features of 14 cases of male PCC, over the age of 20, diagnosed and treated at the Samsung Medical Center (SMC) between 1996 and 2020. Materials and Methods 1. Study population and design A total of 20 male patients with PCC were treated at SMC between 1996 and 2020. Five patients were under the age of 20, and one was diagnosed at another hospital. We excluded these six patients and, finally, 14 male patients with PCC, all aged over 20 years, were included in this retrospective study. All patients were diagnosed on a pathological examination. The medical records of the patients were reviewed, and information on patient death was acquired from census data. The demographic, histological, and clinical characteristics of the patients at diagnosis were described and used for the analysis. Treatment and clinical outcomes of the patients were obtained from medical records. 2. Statistical analysis Statistical analysis was performed to identify the clinical factors affecting overall survival (OS). Briefly, patients were divided into two groups according to clinical characteristics that were expected to influence OS. The OS for each group was estimated using the Kaplan-Meier method. The difference in OS between the two groups was evaluated with the log-rank test. The estimated median OS was used as a representative value for the survival rate. Additionally, the chi-square test was used to confirm association between two different clinical factors used to divide patients into two groups (data not shown). Among many factors, only the association between histologic finding and hemoptysis at the time of diagnosis was statistically significant (p=0.031). All statistical analyses were performed using the SPSS ver. 22 statistical software (IBM Corp., Armonk, NY). Statistical significance was set at p < 0.05. Results 1. Demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis The demographic, histological, and clinical characteristics of 14 male patients with PCC at the time of diagnosis are presented in Table 1. The median age was 33 years (range, 23 to 62 years), and most of the patients were between 20 and 40 years old. Histologically, nine cases (64%) were pure choriocarcinoma, and five cases (36%) were mixed germ cell tumors (MGCTs) including choriocarcinoma and seminoma, germinoma, teratoma, endodermal sinus tumor, and embryonal carcinoma. hCG levels were elevated in all cases, and lactate dehydrogenase levels were elevated in all examined patients (not shown). α-Fetoprotein (AFP) was elevated only in some cases (6/14, 43%). The primary tumor site was the testicles in seven cases (50%), mediastinum in six cases (43%), and brain in one case (7%). In a study by Jiang et al., the testicles were the most common primary tumor site (36.2%), and mediastinal PCC only accounted for 11% of the 113 PCC male patients assessed [7]. Due to the small number of cases in our study, caution is needed in interpreting these results. As previously mentioned, there is a hypothesis that PCC might be a testicular choriocarcinoma metastasis that has either spontaneously regressed or not. Among our cases, one patient described that right testicular swelling occurred about a year ago and had improved at the time of diagnosis. However, testicular sonography revealed that a small testicular mass still existed in his right testis. On the other hand, there was no history of testicular swelling in the other patients with extragonadal PCC. Except for one patient with brain PCC, all other patients had metastatic diseases. The most common metastatic site was the lungs (11/14, 79%), followed by the brain (6/14, 43%), liver (4/14, 29%), and retroperitoneum (4/14, 29%). Initial symptoms varied and were related to the primary and metastatic sites of tumors. Hemoptysis, which is related to the choriocarcinoma syndrome, was present only in some patients with lung metastasis, at the time of diagnosis (6/11, 55%). Interestingly, all patients with hemoptysis at the time of diagnosis had pure choriocarcinoma histology. 2. Treatment and clinical outcomes of 14 male patients with PCC The treatment and clinical outcomes of the patients with PCC are also presented in Table 2. Of the seven patients with testicular PCC, four (4/7, 57%) underwent orchiectomy. In addition, one patient with brain tumor underwent surgical tumor removal, and one patient with small bowel tumor underwent small bowel resection because of excessive bleeding. Excluding these six patients, the remaining patients only underwent biopsy without surgical tumor removal. All patients with PCC received cytotoxic chemotherapy. Various chemotherapeutic regimens were used, such as POMB (cisplatin, vincristine, methotrexate, bleomycin), EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), BEP (bleomycin, etoposide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin). Two patients died soon after starting cytotoxic chemotherapy, and responses to the cytotoxic chemotherapy were assessed in 12 patients. In terms of the best response, eight patients (8/12, 67%) achieved an objective response during cytotoxic chemotherapy. Specifically, three patients achieved a complete response (CR) and five achieved a partial response (PR). Besides, remaining four patients (4/12, 33%) achieved a stable disease (SD) response as the best response to cytotoxic chemotherapy. Among three patients achieving CR during the first course of chemotherapy, two survived for more than five years. Compared to the deceased patients, the two long-term survivors did not have lung metastasis, and their tumor burden was also much lower with fewer metastatic lesions. Furthermore, the two long-term survivors had their primary tumor surgically removed. Specifically, one patient had a brain tumor without a distant metastatic lesion and underwent surgical tumor removal and two courses of cytotoxic chemotherapy due to relapse after the first course of chemotherapy. The other patient had a testicular tumor with only some retroperitoneal lymph nodes involved and underwent radical orchiectomy and one course of cytotoxic chemotherapy. On the other hand, one patient who died after achieving CR during the first course of chemotherapy had a testicular tumor with lung metastasis and hemoptysis. He died due to the progression of lung metastasis and subsequent respiratory failure despite receiving subsequent chemotherapy. Furthermore, all patients who achieved PR or SD to cytotoxic chemotherapy eventually died after developing resistance to chemotherapy. We analyzed the association between clinical characteristics and OS (Table 3). The median OS was similar between the testicular and mediastinal PCC patients (13 months vs. 8 months, p=0.294). The median OS was lower in patients with hCG levels higher than 100,000 mIU/mL compared to those with hCG levels lower than 100,000 mIU/mL (5 months vs. 20 months, p=0.021). This means that patients with lower tumor burden are more likely to live longer because the level of hCG reflects the tumor burden of the choriocarcinoma. On the other hand, the median OS was similar between patients with increased AFP levels and those with normal AFP levels (12 months vs. 13 months, p=0.493). The median OS was lower in patients with pure choriocarcinoma compared to those with MGCTs containing choriocarcinoma, but not statistically significant (8 months vs. 17 months, p=0.092). This result may be derived from the association between hemoptysis at the time of diagnosis and pure choriocarcinoma histology (p=0.031). Indeed, the median OS was lower in patients with hemoptysis at the time of diagnosis compared to those without hemoptysis (4 months vs. 15 months, p=0.045). Additionally, there was no hemoptysis in patients with MGCTs containing choriocarcinoma at the time of diagnosis. Except for one patient with a brain tumor without distant metastatic lesions, the median OS was lower in patients with brain metastasis than in those without brain metastasis (4 months vs. 15 months, p=0.040). In the case of lung metastasis, only one of the deceased patients was free of lung metastasis at the time of diagnosis, but lung metastasis occurred during treatment. These results suggest that survival is shorter in patients with metastasis to organs that are prone to cause clinically threatening symptoms, such as the lungs and brain. Among patients whose response to chemotherapy could be evaluated, median OS was higher in patients who achieved an objective response to cytotoxic chemotherapy compared to those who did not (17 months vs. 4 months, p=0.043). Indeed, one patient with hemoptysis at the time of diagnosis survived for 20 months, probably due to achieving CR with cytotoxic chemotherapy. Discussion To date, there is no standard treatment for the management of male patients with PCC [7]. Cytotoxic chemotherapy is considered an essential treatment, although a variety of treatment strategies, such as surgery and radiotherapy, are also considered. In our study, all 14 patients received cytotoxic chemotherapy, of whom 12 patients with recorded responses achieved either objective response or SD as the best response to chemotherapy. However, 10 of the patients eventually died after developing resistance to chemotherapy. These results suggest that most male patients with PCC will become resistant to chemotherapy during therapy, leading to treatment failure. Immune checkpoint inhibitors (ICIs) have been used in the treatment of many types of cancer [9]. ICIs typically include anti–cytotoxic T-lymphocyte antigen-4 antibodies, anti–programmed death-1 (PD-1) antibodies, and anti–programmed death-ligand 1 (PD-L1) antibodies. Among those, anti–PD-1 antibodies and anti–PD-L1 antibodies target the PD-1/PD-L1 pathway. Blocking the PD-1/PD-L1 inhibitory pathway is thought to activate T cells in the tumor microenvironment, releasing inflammatory cytokines and cytotoxic granules to eliminate tumor cells. Currently, the expression levels of PD-L1 in tumor tissues is considered as a biomarker for predicting the responsiveness to PD-1/PD-L1 blockade therapy. Recently, Veras et al. [10] reported PD-L1 expression in human placentas and gestational trophoblastic diseases, including choriocarcinoma. In human placentas, syncytiotrophoblasts highly express PD-L1, whereas cytotrophoblasts do not, and intermediate trophoblasts express little or no PD-L1. The authors suggested that trophoblastic cells in the placenta contribute to the creation of a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblasts and intermediate trophoblasts. The authors also reported that 22 of 30 choriocarcinoma specimens (73%) showed intense and diffuse PD-L1 immunoreactivity in syncytiotrophoblasts. The other samples showed weak or no PD-L1 staining, which was attributed to the fact that most of the tissues were necrotic, and only a few viable trophoblasts were present. The typical pattern of choriocarcinoma is known as a plexiform arrangement of syncytiotrophoblast cells with mononucleated, mostly cytotrophoblast cells around the foci of the hemorrhage, although some cases may have a relatively inconspicuous syncytiotrophoblast component [4]. These findings suggest that PD-L1 expression from syncytiotrophoblast cells in choriocarcinoma might contribute to immune tolerance against anti-tumor T cells. Several studies have been conducted on the efficacy of PD-1/PD-L1 blockade therapy on trophoblastic neoplasia, including choriocarcinoma [11–13]. Ghorani et al. [11] reported four cases of drug-resistant gestational trophoblastic neoplasia treated with pembrolizumab. In this study, all four cases had PD-L1 overexpression, but three out of four patients achieved remission. It was thought that one patient did not respond to pembrolizumab due to the absence of tumor-infiltrating lymphocytes. Moreover, there are some reports on the efficacy of PD-1/PD-L1 blockade therapy on male PCC. Chi et al. [14] reported that one male patient with PCC achieved a partial but durable response to nivolumab treatment. Loh and Fung [15] reported that one male patient with PCC did not respond to pembrolizumab treatment and progressed rapidly. In these two cases, both PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes were not evaluated. Han et al. [16] reported that one male patient with PCC achieved remission after pembrolizumab treatment combined with cytotoxic chemotherapy. In this study, PD-L1 overexpression on tumor cells was confirmed. On the other hand, in a study by Adra et al. [17], only one of three male PCC patients showed PD-L1 overexpression, and none of the three patients achieved an objective response to pembrolizumab treatment. These results suggest that PD-1/PD-L1 blockade therapy is not effective in all male patients with PCC. It is thought that the therapeutic efficacy of PD-1/PD-L1 blockade varies depending on some clinicopathological features such as PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes. In summary, there is no established standard treatment for male PCC, and cytotoxic chemotherapy is used as a mainstay treatment. Although some patients with low tumor burden and only few metastases can be cured by cytotoxic chemotherapy, most male PCC patients will eventually develop resistance to cytotoxic chemotherapy and die from disease progression. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis might all be poor prognostic factors associated with shorter survival time. ICIs, such as anti–PD-1 antibodies and anti–PD-L1 antibodies, can be a salvage treatment for chemotherapy-resistant male PCC patients. PD-L1 overexpression and the presence of tumor-infiltrating lymphocytes can be used as biomarkers for predicting the efficacy of PD-1/PD-L1 blockade therapy. Table 1 Demographic, histological, and clinical characteristics of 14 male patients with primary choriocarcinoma Case No. Age (yr) Histology hCG (mIU/mL) AFP Primary site Metastatic sites Hemoptysis at the time of diagnosis 1 36 MGCT (IMT:CC:seminoma:EST=50:27:18:5) 135,100 Increased Testis Lung, brain, liver, spleen No 2 62 MGCT (CC:MT:ECA:seminoma=50:30:20:Min) 4,090 Normal Testis Retroperitoneal LN No 3 26 Pure CC 250,000 Normal Testis Lung, liver, retroperitoneal LNs Yes 4 30 Pure CC 631.4 Increased Mediastinum Lung, brain No 5 23 MGCT (CC:germinoma=95:5) 37,510 Increased Brain No No 6 42 Pure CC 270,000 Increased Mediastinum Lung, brain, liver, small bowel Yes 7 38 Pure CC 270,000 Normal Testis Lung, brain, liver, bone marrow, retroperitoneal LNs, others Yes 8 29 MGCT (CC:seminoma=more than 90:less than 10) 200,000 Increased Testis Lung, retroperitoneal LNs No 9 35 Pure CC 53,027 Normal Mediastinum Lung No 10 33 MGCT (no exact data about components of tumor) 158,221.6 Normal Testis Retroperitoneal LNs No 11 33 Pure CC 25,539 Normal Mediastinum Lung Yes 12 28 Pure CC 61,237 Normal Testis Lung Yes 13 24 Pure CC 269,200 Increased Mediastinum Lung, brain Yes 14 38 Pure CC 52,382 Normal Mediastinum Lung, brain No AFP, α-fetoprotein; CC, choriocarcinoma; ECA, embryonal carcinoma; EST, endodermal sinus tumor; hCG, human chorionic gonadotropin; IMT, immature teratoma; LN, lymph node; MGCT, mixed germ cell tumor; Min, minimal; MT, mature teratoma. Table 2 Treatment and clinical outcomes of 14 male patients with primary choriocarcinoma Case No. Surgery Chemotherapy Best response to chemotherapy Survival time 1 Radical orchiectomy POMB×2; BEP×1; PVeBV×1 SD 4 mo 2 Radical orchiectomy BEP×4 CR > 5 yr 3 No EMA×1; CDDP×1; TIP×3; VIP×3; Auto-PBSCT PR 5 mo 4 No BEP×4; TIP×5 SD 12 mo 5 Brain tumor removal BEP×4; VIP×4 CR > 5 yr 6 Small bowel resection BEP×1 NA 0.3 mo 7 No EMA-CO×1 NA 0.6 mo 8 Radical orchiectomy BEP×3; EP×4; CAP×2; TIP×3; Auto-PBSCT PR 17 mo 9 No BEP×4; TIP×6 SD 15 mo 10 No BEP×4; TIP×5; ICE×2 PR 13 mo 11 No BEP×4; TIP×2 SD 4 mo 12 Radical orchiectomy VIP×6; TIP×6; M-VAC×2 CR 20 mo 13 No VIP×8; TIP×1 PR 8 mo 14 No VIP×8 PR > 10 mo Alive Auto-PBSCT, autologous peripheral blood stem cell transplantation; BEP, bleomycin, etoposide, cisplatin; CAP, cyclophosphamide, doxorubicin, cisplatin; CDDP, cisplatin; CR, complete remission; EMA, etoposide, methotrexate, actinomycin D; EMA-CO, etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine; EP, etoposide, cisplatin; ICE, ifosfamide, etoposide, carboplatin; M-VAC, methotrexate, vinblastine, doxorubicin, cisplatin; NA, not assessed; POMB, cisplatin, vincristine, methotrexate, bleomycin; PR, partial remission; PVeBV, cisplatin, etoposide, bleomycin, vinblastine; SD, stable disease; TIP, paclitaxel, ifosfamide, cisplatin; VIP, etoposide, ifosfamide, cisplatin. Table 3 The association between clinical factors and overall survival in male patients with primary choriocarcinoma No. of patients Median overall survival (mo) p-value Primary site Testis 7 13 0.294 Mediastinum 6 8 hCG level Above 100,000 7 5 0.021 Below 100,000 7 20 AFP level Increased 7 12 0.493 Not increased 7 13 Histology Pure CC 9 8 0.092 MGCT 5 17 Hemoptysis at the time of diagnosis Yes 6 4 0.045 No 8 15 Brain metastasis Yes 6 4 0.040 No 7 15 Objective response to chemotherapy (CR or PR) Yes 8 17 0.043 No 4 4 AFP, α-fetoprotein; CC, choriocarcinoma; CR, complete remission; hCG, human chorionic gonadotropin; MGCT, mixed germ cell tumor; OS, overall survival; PR, partial remission. Ethical Statement Study protocol was reviewed and approved by the Samsung Medical Center (Seoul, Korea) institutional review board (2020-05-072-001). Informed consent was waived by the institutional review board due to the retrospective study design. Author Contributions Conceived and designed the analysis: Ji YS, Park SH. Collected the data: Ji YS, Park SH. Contributed data or analysis tools: Ji YS, Park SH. Performed the analysis: Ji YS, Park SH. Wrote the paper: Ji YS, Park SH. Conflicts of Interest Conflict of interest relevant to this article was not reported.	Fatal	ReactionOutcome	CC BY-NC	33285049	20,373,274	2021-07
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain upper'.	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	MAGNESIUM SULFATE, MIDOSTAURIN, SULFAMETHOXAZOLE\TRIMETHOPRIM	DrugsGivenReaction	CC BY	33288862	18,658,791	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'.	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	MAGNESIUM SULFATE, MIDOSTAURIN, SULFAMETHOXAZOLE\TRIMETHOPRIM	DrugsGivenReaction	CC BY	33288862	18,658,791	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Appendicitis'.	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	MAGNESIUM SULFATE, MIDOSTAURIN, SULFAMETHOXAZOLE\TRIMETHOPRIM	DrugsGivenReaction	CC BY	33288862	18,658,791	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chills'.	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	MAGNESIUM SULFATE, MIDOSTAURIN, SULFAMETHOXAZOLE\TRIMETHOPRIM	DrugsGivenReaction	CC BY	33288862	18,658,791	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'.	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	MAGNESIUM SULFATE, MIDOSTAURIN, SULFAMETHOXAZOLE\TRIMETHOPRIM	DrugsGivenReaction	CC BY	33288862	18,658,791	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'.	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	MAGNESIUM SULFATE, MIDOSTAURIN, SULFAMETHOXAZOLE\TRIMETHOPRIM	DrugsGivenReaction	CC BY	33288862	18,658,791	2021-05
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'.	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	MAGNESIUM SULFATE, MIDOSTAURIN, SULFAMETHOXAZOLE\TRIMETHOPRIM	DrugsGivenReaction	CC BY	33288862	18,658,791	2021-05
What is the weight of the patient?	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	100.68 kg.	Weight	CC BY	33288862	18,658,791	2021-05
What was the administration route of drug 'MIDOSTAURIN'?	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Oral	DrugAdministrationRoute	CC BY	33288862	18,658,791	2021-05
What was the outcome of reaction 'Abdominal pain'?	Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362). Introduction Acute myeloid leukemia (AML), the most common acute leukemia, is difficult to treat and has a poor prognosis, with a 5-year survival of ~25% [1, 2]. Multiple factors, including age, performance status (e.g., Eastern Cooperative Oncology Group), and cytogenetic and molecular features, affect treatment decisions and outcomes [3, 4]. Mutations in fms-like tyrosine kinase 3 (FLT3) are among the most common in AML and confer a poor prognosis with poor overall survival (OS) [5–7]. Consequently, these patients, particularly those with internal tandem duplications (ITDs), historically have more frequent and earlier relapses than patients without FLT3 mutations [7, 8]. Midostaurin, a multikinase inhibitor that targets FLT3 and other kinases, was approved for the treatment of adult patients with newly diagnosed, FLT3-mutated AML when combined with intensive induction and consolidation chemotherapy [9]. Approval was based on the phase 3 RATIFY/CALGB 10603 trial, which demonstrated improved survival with the addition of midostaurin to intensive chemotherapy followed by single-agent maintenance therapy in patients aged <60 years with newly diagnosed, FLT3-mutated AML. The RATIFY trial did not allow patients receiving alloHSCT to continue midostaurin [10]. AlloHSCT in first complete remission (CR1) provides patients with FLT3-ITD-positive AML the highest likelihood of sustained remission [11, 12], but relapse rates remain high [13–15]. The prognosis for patients with FLT3-ITD mutations has been poor following standard alloHSCT, primarily because these patients have a higher risk of relapse than patients with FLT3-ITD-negative AML [14–16]. Post-HSCT maintenance therapy with tyrosine kinase inhibitors (TKIs) may improve outcomes in patients with FLT3-mutated AML. In a phase 2 trial (AMLSG 16-10), midostaurin combined with intensive chemotherapy followed by alloHSCT and single-agent maintenance therapy demonstrated improved rates of event-free survival in patients receiving midostaurin compared with historical controls [17]. In AMLSG 16-10, midostaurin was administered as in RATIFY; however, patients who underwent alloHSCT could resume midostaurin as maintenance therapy post-transplant [10, 17]. Data from phase 1 and 2 trials suggest there may be a benefit with sorafenib, another TKI, as maintenance therapy post-HSCT [18–20]. Results from the phase 2 SORMAIN trial, which evaluated post-alloHSCT maintenance with sorafenib, suggested a benefit with sorafenib versus placebo with a median 2-year relapse-free survival (RFS) rate of 85% (95% CI, 70–93%) vs 53% (95% CI, 37–68%), respectively, (hazard ratio [HR], 0.39 [95% CI, 0.183—0.848]; P = 0.013) [20]. Similarly, quizartinib, a FLT3 TKI, was safely administered after alloHSCT in a phase 1 study [21]. Detailed trials evaluating FLT3 TKIs as maintenance therapy are ongoing [22–25]. Here, we report the results of the RADIUS trial investigating whether the addition of midostaurin to standard-of-care (SOC) treatment post-alloHSCT improves RFS over SOC alone in patients with FLT3-ITD-positive AML. Patients and methods Study design RADIUS (NCT01883362) was a phase 2, randomized, open-label trial of SOC with or without midostaurin in patients (aged 18–70 years) with documented FLT3-ITD-positive AML who had undergone a protocol-specified conditioning regimen before alloHSCT in CR1 (following hematologic recovery, transfusion independence, and controlled graft-vs-host disease [GVHD]). Patients were enrolled after engraftment and randomized 1:1 within 28 to 60 days after alloHSCT to receive SOC ± midostaurin (50 mg twice daily in twelve 4-week cycles). SOC was dictated by the treating physician but excluded alternate TKI therapy. Currently, SOC therapy varies per treating institution in the post-alloHSCT setting. SOC therapy includes anti-infective prophylaxis and treatment as well as GVHD prophylaxis and treatment along with supportive care. Anti-infective and GVHD prophylaxis treatments were based on institutional guidelines. Patients were assessed for relapse and survival through 24 months post-alloHSCT and/or until the end of the study. Patient visits occurred monthly for 1 year during treatment and every other month during the 24-month follow-up. Adverse events (AEs) were tracked for 30 days after treatment ended and assessed per the Common Terminology Criteria for Adverse Events version 4.0 [26]. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and was approved by institutional review boards at participating institutions. All patients provided written informed consent. Endpoints The primary endpoint was RFS (time from transplant to relapse or death due to disease) 18 months after alloHSCT. Key secondary endpoints were safety, OS (time from transplant to the date of death from any cause), and RFS 24 months after alloHSCT. Pharmacokinetics and in vivo FLT3 inhibition by FLT3 plasma inhibitory activity (PIA) assay were assessed as preplanned exploratory endpoints (see Supplementary methods). FLT3 inhibition and FLT3 ligand levels were evaluated on the basis of phosphorylated FLT3 (P-FLT3) and FLT3 ligand levels in the plasma [27]. The incidence and severity of GVHD were also exploratory study objectives. The percentage of patients developing acute or chronic GVHD (categorized according to the National Institutes of Health Consensus Development Project Working Group criteria [28]) and grade of GVHD were collected throughout the study by local assessment. GVHD by category and organ class was assessed at each study visit. Statistical analysis RADIUS was an exploratory, signal-finding study not powered to detect a statistical difference between treatment arms. A sample size of 60 was calculated to detect a 50% reduction in the risk of relapse with 71% power, assuming a 15% incidence of relapse in the midostaurin arm. For time-to-event analyses, Kaplan–Meier curves were used to estimate survival distributions. A Cox proportional hazards model was used to estimate the HR and associated 95% CIs. Results Patients Between February 5, 2014, and June 13, 2016, 74 patients were screened and 60 patients (30 per arm) were randomized at 18 sites in the United States and 1 site in Canada (Fig. 1 and Table S1). All patients were in CR1 prior to transplant; 18 patients (30%) received transplant directly following induction, 39 (65%) of patients had received consolidation without additional maintenance, and 3 (5%) of patients had received pretransplant maintenance. All patients had completed a protocol-specified conditioning regimen before alloHSCT (Table S2). Overall, 30 patients completed the per-protocol 12 cycles of therapy (midostaurin + SOC: 16 patients [53%]; SOC: 14 patients [47%]). The number of patients discontinuing early from the study was comparable between arms (midostaurin + SOC, n = 13; SOC, n = 15); however, the reasons for treatment discontinuation differed by arm, with AEs being the most common reason in the midostaurin arm (27% vs 3%) and consent withdrawal being the most common reason in the SOC arm (7% vs 20%). Patients who withdrew from treatment were to return for relapse and follow-up assessments and were not considered withdrawn from the study. Patients who withdrew consent were censored at the time of withdrawal. Patient demographics, baseline characteristics, and transplant characteristics are shown in Table 1. Most patients (midostaurin + SOC, 100%; SOC, 90%) had de novo AML. The 2 arms were balanced with regard to age, sex, and race.Fig. 1 CONSORT diagram. AE adverse event, alloHSCT allogeneic hematopoietic stem cell transplant, SOC, standard of care. aA single patient might have had >1 reason for screen failure. bEarly termination due to work schedule conflicts. cPatients lost to follow-up (n = 2), early termination due to hospitalization at outside facility (n = 1), and early termination due to large travel distance (n = 1). Table 1 Baseline patient and transplant characteristics. Full analysis set Midostaurin + SOC (n = 30) SOC (n = 30) Median age (range), yearsa 48 (20–61) 56 (20–68) Sex, n (%)b Male 16 (53) 18 (60) Female 14 (47) 12 (40) Race, n (%)c White 27 (90) 27 (90) Other 3 (10) 3 (10) AML status at initial diagnosis, n (%) De novo 27 (90) 30 (100) Secondary to AHD 1 (3) 0 Therapy related 2 (7) 0 Median peripheral WBC count (range), × 109/L 48 (<1–278) 55 (<1–344) Presence of FLT3-TKD mutation Yes 3 (10) 2 (7) No 17 (57) 20 (67) Unknown 10 (33) 8 (27) Purpose of pre-HSCT treatment, n (%) Induction 30 (100) 30 (100) Consolidation 22 (73) 20 (67) Maintenance 2 (7) 1 (3) Median time to randomization (range), days 54 (34–61) 54 (30–64) Donor type, n (%) Syngeneic 0 1 (3) Allogeneic, matched relatedd 10 (33) 14 (47) Allogeneic, matched unrelatedd 20 (67) 15 (50) Stem cell source, n (%) Peripheral blood 29 (97) 28 (93) Bone marrow 1 (3) 2 (7) AHD antecedent hematologic disorder, AML acute myeloid leukemia, FLT3 fms-like tyrosine kinase 3, HLA human leukocyte antigen, HSCT hematopoietic stem cell transplant, SOC standard of care, TKD tyrosine kinase domain, WBC white blood cell. aP = 0.14; 2-sample t-test. bP = 0.60; Fisher exact test. cP = 0.72; Fisher exact test. dMatched donors had HLA typing to include an 8/8 or 7/8 allele match rate at HLA-A, -B, -C, and -DRB1. A single mismatch was allowed. Efficacy The estimated RFS at 18 months (95% CI) was 89% (69–96%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.46 [95% CI, 0.12–1.86]; P = 0.27) (Fig. 2A). There were 3 RFS events in the midostaurin arm and 6 RFS events in the SOC arm at 18 months. The predicted relative reduction in the risk of relapse with the addition of midostaurin was 54% at 18 months post-alloHSCT.Fig. 2 Outcomes after alloHSCT. Kaplan–Meier curves of A RFS by treatment arm at 18 months after undergoing alloHSCT and B OS by treatment arm at 24 months after undergoing alloHSCT. Blue, midostaurin + SOC; red, SOC. Tick marks indicate censoring of data. alloHSCT allogeneic hematopoietic stem cell transplant, HR hazard ratio, OS overall survival, RFS relapse-free survival, SOC standard of care. aMedian RFS was not reached. bLog-rank P value. cMedian OS was not reached. At 24 months, addition of midostaurin to SOC continued to demonstrate reduced risk of relapse and prolonged survival compared with SOC alone (Figs. 2B and S1). At the time of final analysis (i.e., when all patients who remained on the study had reached 24 months post-alloHSCT), the median RFS and OS were not reached in either treatment arm. There were 4 relapses (13%) in the midostaurin arm vs 5 relapses (17%) in the SOC arm; median time to relapse from transplant was similar across both arms (median [range]; midostaurin + SOC, 323.5 days [69–1028 days]; SOC alone, 323 days [94–456 days]). The estimated 24-month RFS (95% CI) was 85% (64–94%) with midostaurin and 76% (54–88%) with SOC alone (HR, 0.60 [95% CI, 0.17–2.14]; P = 0.4297), and the relative reduction in the risk of relapse with the addition of midostaurin remained high at 40%. Survival outcomes also improved; the estimated 24-month OS (95% CI) was 85% (65%-94%) with midostaurin and 76% (54%-89%) with SOC alone (HR, 0.58 [95% CI, 0.19–1.79]; P = 0.34), which is a 42% reduction in the risk of death with the addition of midostaurin (albeit not statistically significant). Eight patients died in the SOC arm vs 5 patients in the midostaurin arm; relapse accounted for a similar fraction of deaths in each arm. Details of post-relapse treatment were not captured. A total of 7 patients died due to reasons other than relapse: 5 in the SOC arm and 2 in the midostaurin arm; these patients were censored at the date of death. Non-relapse mortality was due to study indication (n = 2) and 1 instance each of cardiac arrest, GVHD, hepatic failure, cardiopulmonary arrest, and encephalitis infection. Pharmacokinetics and PIA assay The pharmacokinetics of midostaurin and its main metabolites (CGP62221 and CGP52421) were evaluated in 29 patients. The mean plasma concentration of midostaurin reached a maximum duringcycle 1 day 15, where as CGP52421 and CGP62221 peaked at cycle 3 day 1; all reached steady-state levels at cycle 4 (Fig. S2). Among patients who received midostaurin, 28 were evaluable using the PIA assay. The degree of P-FLT3 inhibition was greatest during the first 2 cycles of therapy (Fig. 3A, B). In an exploratory biomarker analysis that assessed the correlation between plasma levels of midostaurin and its primary metabolites with the degree of FLT3 inhibition (i.e., lower levels of P-FLT3), early inhibition of FLT3 correlated inversely with drug levels (Fig. 3B). Peak FLT3 inhibition occurred at cycle 3 day 1; this time point was chosen for the correlative analysis.Fig. 3 Correlation between exploratory biomarker analyses and clinical outcomes. A Median FLT3 ligand levels and B median P-FLT3 levels relative to baseline and concurrent combined levels of midostaurin and its metabolites in patients who received midostaurin + SOC. Median P-FLT3 levels were 70% of baseline at C3D1. C RFS and D OS at 24 months after alloHSCT in patients who received midostaurin + SOC stratified by P-FLT3 level (<70% vs >70%). C cycle; D day; FLT3, fms-like tyrosine kinase 3; M midostaurin, P-FLT3 phosphorylated FLT3, OS overall survival, RFS relapse-free survival, SOC standard of care. aFor this analysis, RFS was defined as time from transplant to relapse or death from any cause. bLog-rank P value vs SOC (n = 28). cPatients who reached C3D1 and received midostaurin + SOC (n = 28) were stratified according to FLT3 inhibition levels above or below the median (median P-FLT3, 70%). FLT3 inhibition was higher in patients with P-FLT3 levels <70% of baseline. dP-FLT3 > 70% includes patients with missing P-FLT3 at C3D1. In patients receiving midostaurin (n = 28), the median P-FLT3 level at cycle 3 day 1 was 70% of baseline P-FLT3 levels. Thus, 14 of these patients had more effective inhibition of FLT3 activity (i.e., P-FLT3 levels <70% of baseline) on cycle 3 day 1 with P-FLT3 levels ranging from 20% to 69%. Of these 14 patients, 10 completed all 12 cycles of midostaurin therapy (Fig. S3). Among the remaining 14 patients who had less effective inhibition of FLT3 activity (i.e., P-FLT3 levels >70% of baseline), P-FLT3 was not measured at cycle 3 day 1 in 8 patients (6 were not receiving midostaurin on cycle 3 day 1). Six of 14 patients completed 12 cycles of midostaurin therapy and had P-FLT3 levels ranging from 74% to 100%. These higher P-FLT3 levels indicate less effective FLT3 inhibition, possibly resulting from the biological response of the patient to midostaurin or likely related to patient adherence to midostaurin, indicating the importance of proactive AE management to support patients throughout treatment. Stratifying patients who received midostaurin by levels of FLT3 inhibition above or below the median revealed an association with clinical outcomes. Higher levels of FLT3 inhibition correlated with prolonged RFS, a reduced risk of relapse (P = 0.06), and significantly improved survival (P = 0.048) (Fig. 3C, D). Patients with less FLT3 inhibition had a similar risk of relapse and survival rate to those observed in patients receiving SOC alone (P = 0.9 and P = 0.92, respectively). Safety With midostaurin + SOC and SOC alone, AEs occurred in 100% and 87% of patients, respectively (Table 2). Most AEs in both arms were grade 1/2. The most common AEs were low-grade gastrointestinal AEs (grades 1–3, midostaurin arm vs SOC arm): vomiting (73% vs 23%), nausea (67% vs 27%), and diarrhea (49% vs 23%). Gastrointestinal AEs were more common in the midostaurin arm than in the SOC arm. The most common grade 3/4 laboratory abnormalities, increased alanine aminotransferase, increased aspartate aminotransferase, and decreased neutrophils, occurred in both arms. Serious AEs (Table 3) occurred in 57% of patients with midostaurin and 30% of patients with SOC alone. The most common serious AEs (midostaurin arm vs SOC arm) were diarrhea (13% vs 7%), nausea and vomiting (both, 3% vs 10%), and pyrexia (7% vs 7%).Table 2 Most common AEs (occurring in ≥15% of patients). AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Any grade Grade ≥ 3 Any grade Grade ≥ 3 Vomiting 7 (23) 1 (3) 22 (73) 2 (7) Nausea 8 (27) 3 (10) 20 (67) 1 (3) Diarrhea 7 (23) 1 (3) 12 (40) 3 (10) Fatigue 9 (30) 0 8 (27) 1 (3) Peripheral edema 9 (30) 0 8 (27) 0 Headache 7 (23) 0 8 (27) 0 Cough 6 (20) 0 8 (27) 0 ALT increased 7 (23) 4 (13) 6 (20) 3 (10) Anemia 6 (20) 2 (7) 7 (23) 3 (10) AST increased 8 (27) 4 (13) 5 (17) 2 (7) Pruritus 6 (20) 0 7 (23) 3 (10) Dry eye 6 (20) 0 5 (17) 0 Pyrexia 5 (17) 1 (3) 4 (20) 0 Rash 6 (20) 0 6 (17) 0 Tremor 4 (13) 0 7 (23) 0 Dyspnea 7 (23) 1 (3) 3 (10) 0 Insomnia 6 (20) 0 4 (13) 0 Neutrophil count decreased 3 (10) 2 (7) 7 (23) 4 (13) Arthralgia 6 (20) 1 (3) 3 (10) 0 Dizziness 6 (20) 0 3 (10) 0 Hypertension 6 (20) 4 (13) 3 (10) 0 Upper respiratory tract infection 6 (20) 0 3 (10) 0 AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, SOC standard of care. Table 3 Serious AEs occurring in ≥1 of patients overall. AE, n (%) Midostaurin + SOC (n = 30) SOC (n = 30) Diarrhea 4 (13) 2 (7) Nausea 1 (3) 3 (10) Vomiting 1 (3) 3 (10) Pyrexia 2 (7) 2 (7) Deep vein thrombosis 1 (3) 2 (7) Febrile neutropenia 1 (3) 2 (7) Anemia 2 (7) 1 (3) Acute kidney injury 0 2 (7) Abdominal pain 1 (3) 1 (3) Parainfluenza virus infection 1 (3) 1 (3) AE adverse event, SOC standard of care. Median midostaurin exposure was 10.5 months (range, 0.2–11.5 months; defined by time of last midostaurin dose); 16 patients completed all 12 cycles of treatment. The median dose intensity was 93 mg/day (range, 25–100 mg/day). Dose adjustments were required per protocol in 19 patients (63%), most commonly due to AEs (84%). AEs leading to dose adjustment in ≥10% of patients included vomiting (27%), nausea (20%), and aspartate aminotransferase levels increased (10%). One patient was reported to have received a modified dose of midostaurin due to concomitant posaconazole, a cytochrome P450 3A4 inhibitor, per protocol. AEs resulted in discontinuation from the study in 9 patients: 8 (27%) in the midostaurin arm and 1 (3%) in the SOC arm. The 8 patients in the midostaurin arm who discontinued treatment had 9 events: nausea (n = 3), vomiting (n = 2), liver function test levels increased (n = 2), pulmonary mycosis (n = 1), and pneumonitis (n = 1). The patient in the SOC arm discontinued from the study due to hypoxia. Twelve patients died on study during the follow-up phase (midostaurin + SOC, n = 4; SOC, n = 8). Death due to AML disease progression occurred in 2 patients receiving midostaurin and 4 receiving SOC alone. The addition of midostaurin to SOC did not result in an increase in the severity or rate of acute or chronic GVHD (Table 4). Rates of GVHD, as determined by local assessment, were similar between the midostaurin and SOC arms (overall, 70% vs 73%; acute, 53% vs 50%; and chronic, 37% vs 33%, respectively). Ninety-seven percent of patients received concomitant medication for the management of GVHD, including 28 (93%) in the midostaurin arm and 30 (100%) in the SOC arm. The most common concomitant medications typical of GVHD management were calcineurin inhibitors (85%), glucocorticoids (57%), moderately potent corticosteroids (18%), and selective immunosuppressants (17%) (Table S3).Table 4 Incidence of GVHD. GVHD, n (%)a Midostaurin + SOC (n = 30) SOC (n = 30) Acute 15 (50) 16 (53) Grade I 7 (23) 4 (13) Grade II 8 (27) 10 (33) Grade III 0 2 (7) Grade IV 0 0 Chronic 9 (30) 10 (33) Mild 2 (7) 5 (17) Moderate 5 (17) 4 (13) Severe 2 (7) 1 (3) GVHD graft-vs-host disease, SOC standard of care. aPatients could be counted in multiple categories. The most common organ toxicity due to GVHD was localized to the skin and affected 50% of patients in the midostaurin arm and 47% of patients in the SOC arm (Fig. S4). All patients with skin involvement in the midostaurin arm had stage 1 or 2 disease, whereas 2 patients in the SOC arm experienced stage 3 disease. Neither arm reported stage 4 organ involvement. Upper gastrointestinal toxicity was similar in both groups and did not exceed stage 1. Lower gastrointestinal toxicity was reported only in patients in the SOC arm and was primarily stage 1. Discussion This is the first randomized study of midostaurin as maintenance therapy after alloHSCT. We show that for patients with FLT3-ITD-positive AML in CR1, a defined course of up to 12 months of maintenance therapy with midostaurin was safely added to SOC after recovery from alloHSCT and improved RFS at 18 months after alloHSCT by 13% (over SOC alone). Although the study was not powered to detect a treatment difference, there was a trend toward benefit with midostaurin for all efficacy endpoints evaluated. The survival outcomes in all participants in this study were better than anticipated for this high-risk leukemia population. Historically, the expected 2-year OS with SOC was closer to 60% compared with 76% observed in this study [15]. The stringent enrollment criteria, including recovery of counts (i.e., absolute neutrophil count >1000/μL and platelet count ≥20,000/μL without platelet transfusion) by day 42, ability to start treatment by day 60 post- alloHSCT, and no active, advanced, acute GVHD, may have contributed to the survival outcomes observed for all participants in this study. Moreover, the median time from the date of alloHSCT to initiation of study drug for both arms was 54 days; patients who had morphological relapse before that date were ineligible. Consistently, factors related to these inclusion/exclusion criteria, such as unacceptable test procedure results (8%) and unacceptable medical history/concomitant diagnosis (4%), were common reasons for screen failure, though the overall rate of screen failures (14 of 74 patients screened [19%]) was relatively low. Censoring of patients at the date of death due to non-relapse mortality may also have contributed to survival rates, particularly given the small patient population in this study. Similarly, patients were not stratified by European LeukemiaNet or National Comprehensive Cancer Network molecular risk classification due to the size of the study; thus, enrollment of patients with favorable molecular risk factors may also have affected the survival rates observed. Correlative analysis suggests that patients who tolerated midostaurin and remained on therapy, as demonstrated by relatively higher levels of P-FLT3 inhibition, may have sustained benefit and long-term outcomes. The PIA assay allows for an indirect measurement of the phosphorylation of FLT3. P-FLT3 inhibition to <70% of baseline was achieved by 50% of patients receiving midostaurin and was associated with improved RFS and OS, indicating that inhibiting FLT3, even modestly, can have clinical benefit. Treatment adherence was not uniform in all patients receiving midostaurin, possibly due to tolerability (e.g., gastrointestinal toxicity). Prophylactic support, including antiemetics, in the management of gastrointestinal toxicities was crucial in keeping patients on therapy to provide the clinical benefit suggested by these data. Thus, increases in gastrointestinal toxicities were primarily low grade and manageable, consistent with other reports with single-agent midostaurin [29, 30]. Addition of midostaurin to SOC did not increase rates or severity of GVHD. Although the PIA assay is not used in clinical practice, FLT3 inhibition measured by this assay has tightly correlated with clinical activity across a broad array of FLT3 inhibitors [27, 31–34]. The results from the exploratory analysis in this study suggest that midostaurin therapy after alloHSCT may provide high levels of FLT3 inhibition in the long term in patients who remain on treatment, though further validation is required. These data are consistent with the safety profile of midostaurin in patients with FLT3-ITD AML. In line with the AMLSG 16-10 study [17], the median time of midostaurin exposure during maintenance was similar (9 months in AMLSG 16-10 and 10 months in RADIUS); discontinuation due to toxicity was more common in AMLSG 16-10 (55%) than in RADIUS (27%), which may be explained by the stringent inclusion criteria of RADIUS. However, both studies demonstrated the safety and feasibility of midostaurin maintenance therapy. Post-alloHSCT maintenance therapy with FLT3 TKIs, including midostaurin, is a viable treatment for reducing the risk of relapse in patients with FLT3-ITD AML. We anticipate that this study will provide a landmark for future studies, as the population had no pretransplant TKI exposure. These results complement those of the AMLSG 16-10 trial, which demonstrated improved event-free survival for patients with FLT3-ITD AML who received pretransplant midostaurin and began midostaurin within 100 days post-transplant compared with patients who only received pretransplant midostaurin [17]. Evidence from the present study and AMLSG 16-10 suggest that midostaurin maintenance therapy may be most appropriate for patients aged 18–70 years with FLT3-ITD AML who have undergone alloHSCT in CR1 and can begin midostaurin therapy quickly (within 100 days, ideally <60 days). With the approval of midostaurin as up-front therapy for FLT3-ITD AML, new trials are emerging to better clarify the role of post-transplant TKI therapy in patients with deeper molecular remission, such as the large, phase 3, multinational, randomized trial assessing gilteritinib vs placebo as post-transplant adjuvant therapy for patients with FLT3-ITD AML in CR1 (BMT-CTN 1506; NCT02997202). As available treatment options increase, more detailed scrutiny of the risk-benefit profiles of these targeted agents is likely to be required. With a post-transplant 2-year OS of ~80%, this study highlights the impact of recent advances in the management of FLT3-ITD AML on survival outcomes. Because FLT3-mutated AML has a higher risk of relapse than FLT3-mutation-negative AML, the addition of midostaurin maintenance therapy post-HSCT may be a viable option to reduce the risk of relapse in some patients after alloHSCT. These results provide evidence of clinical benefit and an estimate of treatment effect that could inform larger-scale studies in the future. Supplementary information Supplemental Material Supplementary information The online version of this article (10.1038/s41409-020-01153-1) contains supplementary material, which is available to authorized users. Acknowledgements The authors would like to thank the patients and the investigators who participated in the RADIUS study. Medical editorial assistance was provided by JoAnna Anderson, Ph.D., and Amy Ghiretti, Ph.D., of ArticulateScience LLC, and was supported by Novartis Pharmaceuticals Corporation. This study was funded by Novartis Pharmaceuticals Corporation. Compliance with ethical standards Conflict of interest RTM discloses honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics; Board of Directors membership at Novartis Pharmaceuticals Corporation; consultancies with Incyte and Juno Therapeutics; and patents and royalties from Athersys, Inc; as an OHSU employee who provided and received payment for consultancy services to Novartis Pharmaceuticals Corporation, this potential conflict of interest has been reviewed and managed by OHSU. ML discloses consultancy with Novartis Pharmaceuticals Corporation, Astellas, and Daiichi Sankyo; research funding from Novartis Pharmaceuticals Corporation, Astellas, and Fujifilm; and honoraria from Novartis Pharmaceuticals Corporation. MMP discloses advisory board membership with Stemline. BLS discloses consultancy with Acceleron, Incyte, Agios, Celgene, and Alexion and research funding from Novartis Pharmaceuticals Corporation and Celgene. SRM has nothing to disclose. AD discloses consultancies with Kite Therapeutics and Novartis Pharmaceuticals Corporation. SDR has nothing to disclose. DDHK discloses consultancies with Novartis Pharmaceuticals Corporation, Bristol-Meyers Squibb, Paladin, and Pfizer and honoraria and research funding from Novartis Pharmaceuticals Corporation and Bristol-Meyers Squibb. DH and TR have nothing to disclose. KH discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Regeneron Pharmaceuticals, Inc. GB and DP disclose employment with Novartis Pharmaceuticals Corporation. PR discloses former employment with Novartis Pharmaceuticals Corporation and current employment with Target CW. HFF discloses honoraria from Pfizer and Sanofi and speakers’ bureau membership with Sanofi. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.	Recovered	ReactionOutcome	CC BY	33288862	18,658,791	2021-05

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