instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6
values | meta_inputlicense stringclasses 6
values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Encephalopathy'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypophysitis'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypothyroidism'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Inappropriate antidiuretic hormone secretion'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Meningitis aseptic'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Microangiopathic haemolytic anaemia'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myalgia'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephritis'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Uveitis'. | Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?
BACKGROUND
There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge.
METHODS
We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy.
RESULTS
Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former.
CONCLUSIONS
Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
1. Introduction
The adoption of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies. In particular, survival outcomes have improved markedly for previously morbid advanced stage non-small cell lung cancer, melanoma, and other malignancies when treated with immune checkpoint inhibitors (ICIs) as a form of cancer immunotherapy [1,2]. There are 6 main programmed death (PD)-1/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors in clinical practice that have been granted approval by the U.S. Food and Drug Administration (FDA) in recent years: pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab. Each of these ICIs has been approved in specific stages of specific malignancies with the exception of pembrolizumab; which has a tumor agnostic biomarker indication that can be met with microsatellite-instability (MSI)-high status. Studies investigating factors that predict immune-related adverse events (irAEs) have been limited to non-small cell lung cancer, melanoma, and renal cell carcinoma. Furthermore, they have been primarily limited to patients receiving ipilimumab, nivolumab, or pembrolizumab [3].
The primary response to T-dependent antigens during humoral immunity includes B-lymphocytes initiating a cascade of events that culminate in the circulation of many B-memory cells and T4-memory cells [4]. These circulating cells play a major role in the anamnestic response to future similar antigen exposure and does so, in part, by migrating to the bone marrow where they continue to secrete antibodies up to a period of months or even years after the last detected antigen has been destroyed [5]. This period of anamnestic immune response varies from patient to patient. As a result, there is potential benefit to prolonging the effects of immunotherapy in patients with irAEs by extending this finite period of anamnestic humoral immune response. As clinicians have gained more experience incorporating immunotherapy into clinical practice, observations have been made to the positive correlation between developing immune related adverse events and overall patient outcomes [6,7]. There are few studies examining whether there are significant changes in patient outcomes in cases where immunotherapy is resumed after an irAE [8]. Although it has been suggested that patients with cancer sustain durable responses from immunotherapy after overcoming these adverse events and not resuming therapy, there is insufficient longitudinal data to support this clinical practice. The possibility of the immunotherapy microenvironment “settling down” after several months or years cannot be readily discounted. Such a possibility could endanger any gains obtained from immunotherapy and lead to relapse of disease.
Checkpoint inhibitors are believed to improve survival outcomes in patients with metastatic non-small lung cancer and metastatic melanoma through a myriad of “revving up” the immune system to preferentially target tumor cells. A consequence of this mechanism of action, and a simple marker of patient response to immunotherapy, is a grade 1 through 4 irAE. There are various well described adverse events associated with immune checkpoint inhibitors involving largely all the internal organs [9]. IrAEs that require treatment with steroids and other immunomodulating therapies do not necessarily affect patient outcomes adversely [6,10]. Corticosteroids are a mainstay of American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines for managing a majority of irAEs [11]. Corticosteroids have anti-inflammatory and immunosuppressive effects that can interfere with the innate and adaptive immune system. As a result, patients treated with corticosteroids at doses equal to or higher than 10 mg/day of prednisone (or its equivalent) have been systematically excluded from immunotherapy clinical trials.
There are significant disparities in cancer incidence and mortality in the Appalachian West Virginia state in comparison to the rest of the nation. In this single center cohort study, our objective was to investigate the patient characteristics and outcomes who developed irAEs under treatment with ICIs, including anti-PD-L1, anti-PD-1, anti-CTLA-4, combination ICI, with or without combination with non-immune chemotherapeutics or targeted therapies for either solid or hematologic malignancies. Specifically, we aimed to investigate whether there were differences in outcomes between patients who were rechallenged after an irAE and those who experienced no irAEs or those who had ICIs discontinued. IrAE and ICI-specific characteristics were also evaluated.
2. Methods
2.1. Study Design and Participants
This retrospective, single center study was approved by the Institutional Review Board of West Virginia University. Patients with active malignancies treated with immune checkpoint monotherapy anti-PD-1/PD-L1 antibodies (e.g., pembrolizumab, nivolumab, durvalumab, atezolizumab, or avelumab) or in combination with anti-CTLA-4 therapy (ipiliumumab), or other established therapies were included. Patients with a histopathologic diagnosis of active malignancy, at least 18 years of age, received at least one cycle of an aforementioned ICI from January 2011 and September 2019 at the West Virginia University Mary Babb Randolph Cancer Center, WVU Cancer Institute (Morgantown, WV, USA) and developed at least one irAE during this time were included in this study. In addition, a matching cohort of 131 patients without an irAE were selected from the database during this timeframe to serve as a comparator arm. Patients with irAEs were dichotomously classified based on subsequent re-exposure to ICI: (1) rechallenged patients had either (a) no interruption in ICI or (b) had reinitiated therapy after interruption; and (2) non-reinitiated patients had no further exposure to ICI after the irAE-related interruption. The definition and grade of an irAE was defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0). The data was obtained from the cancer center’s electronic medical record and the data stored in a secure web application, REDCap, via a de-identified, and password-protected fashion.
2.2. Procedures
All patients had data collected on demographics, histology, stage at diagnosis, tumor grade, total number of ICI cycles given, total duration on ICI, immunosuppressive therapy for the irAE used, date of diagnosis, date of start of ICI, date of radiologic progression/biopsy proven progression, date of death, disease status after intended ICI completion, substance abuse, Eastern Cooperative Oncology Group performance status, central nervous system (CNS) metastasis status and whether related steroid use was required, steroid or systemic antibiotic use 30 days before ICI initiation, and PD-L1 status per tumor proportion scoring. Disease status was assessed as per the response evaluation criteria in solid tumors (RECIST) 1.0 criteria. Comorbid conditions were defined as obesity (BMI ≥ 30), hypertension, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, any autoimmune related conditions, coronary artery disease, cirrhosis/liver disease, chronic kidney disease, and other non-skin malignancies.
Patients who developed an irAE had the following data obtained: need for immunosuppressive treatment as related to irAE, type of immunosuppressive therapies, type of irAE and its grade, identity of immunotherapy used on rechallenge, date of any second or third recurrent irAE, date of initial and subsequent ICI resumption, and grade of second or third recurrent irAE. Patients were stratified by irAE status and ICI rechallenge status (rechallenged with interruption, rechallenged without interruption, and therapy discontinued without reinitiation post-interruption) following irAE.
2.3. Outcomes
Duration from irAE to ICI resumption was defined as the median days from irAE to the first date of ICI resumption. Median observed period was defined as the median days from the first ICI cycle to the cut off period of 30 September 2019. Median duration of initial ICI therapy was defined as the median days from initial ICI cycle to the last cycle prior to an irAE. Median duration of total ICI therapy was defined as the median days from initial ICI therapy to the last ICI cycle administered. Overall survival was defined from time of ICI initiation to death from any cause or censored at last follow-up by 30 September 2019. Response evaluation was investigator-assessed using response evaluation criteria in solid tumors principles (RECIST v1.1).
2.4. Statistical Analysis
Patient and disease characteristics were summarized as median and range for continuous variables, and as numerical values/frequencies for categorical variables. The characteristics of patients and initial irAEs were compared between the reinitiated and non-reinitiated groups by Fisher’s Exact test for categorical variables and Wilcoxon’s Rank Sum test for continuous variables. The Cox multivariate proportional analysis model was used to analyze the hazard ratio and effect of checkpoint inhibitor reinitiation status on overall survival, adjusting for covariates. A time to event analysis was incorporated. Comparisons of medians were carried out using the Wald test, and differences with p ≤ 0.05 values were regarded as statistically significant. The distribution of overall survival was evaluated with the Kaplan–Meier methodology. The statistical analysis was performed using SAS® software (Version 9.4, SAS Institute Inc., Cary, NC, USA).
3. Results
A total of 548 patients who received ICI therapy were screened for study inclusion; 14 patients were excluded due to being lost to follow-up (n = 13) and less than 18 years of age (n = 1). We identified 133 (25%) patients who developed at least 1 irAE of any grade and a matching 131 patients (25%) cohort that did not; demographics and clinicopathologic characteristics are shown in Table 1. The median age was 65 years (IQR, 59–73 years) versus 63 years (IQR, 55–69 years). Most patients had an ECOG of 0–1 in both cohorts (81% versus 77%). Lung was the most common malignancy type (40% versus 45%) followed by melanoma (29% versus 19%) and genitourinary (11% vs. 10%). CNS disease was present in 35 patients (26%) versus 42 patients (32%), of which 31 patients (89%) versus 34 patients (76%) required palliative steroid treatment.
3.1. Initial ICI in Patients with an irAE
The median observation period was 14.5 months (IQR, 6–25) versus 13.3 months (IQR, 4–23). Initial ICI therapy was a PD-1 inhibitor in 87 patients (65%) versus 109 patients (83%), a CTLA-4 inhibitor in 10 patients (8%) versus 9 patients (7%), a combination in 20 patients (15%) versus 1 patient (1%), and a PD-L1 inhibitor in 16 patients (12%) versus 12 patients (9%). 33 patients (25%) versus 28 patients (21%) had steroid use within 30 days of ICI initiation. 31 patients (23%) versus 27 patients (21%) required antibiotic use within 30 days of ICI initiation. 32% of evaluable patients with irAE had a PD-L1 status ≥50% compared to 21% without an irAE.
3.2. Initial and Sequential irAEs
The median duration from initial irAE to ICI reinitiation was 28 days (IQR, 16–44; Table 2). 70 patients (61%) developed grade 2 irAE and 45 patients developed grade 3 or 4 irAE (34%). 98 (74%) patients were rechallenged (with or without interruption) with further ICI after initial irAE. The same ICI was used for 83 patients (85%) upon reinitiation, of which 79 patients were administered an anti-PD1 inhibitor. The median duration from ICI reinitiation to 2nd irAE was 3 months (IQR, 1–6). 41 patients (42%) developed a second irAE, a majority being grade 1–2 (71%). Only 11 (27%) patients with a second irAE had the same irAE upon rechallenge. The median duration from initial ICI reinitiation to 3rd irAE was 10 months (IQR, 6–18). 7 patients (5%) developed a third irAE, of which 4 patients developed the same grade and type of irAE as either of the first two irAE. Out of 80 patients (60%) that required immunosuppressive therapies, a majority (79%) were treated with oral or intravenous corticosteroids.
The three most common irAEs after the initial rechallenge were thyroid dysfunction, diarrhea/colitis, and rash (Supplemental Table S1). The least common irAEs included nephritis and myalgia. In patients who had an irAE and were rechallenged with/without ICI interruption, the median duration of initial irAE was documented to be a median of 2 months (IQR 1–4) and occurred sooner than patients with therapy discontinuation without reinitiation (median, 3.5 months; IQR 2–8 months; p = 0.02). There were no statistical differences in the median observation period between the two groups (Table 3). The grade of initial irAE were more severe in the non-reinitiated group (p < 0.001) and required a greater proportion of patients to be treated with immunosuppression (51% in the rechallenged versus 86% in non-reinitiated, p < 0.0001). The median overall survival was 10.1 months (IQR, 6.5–13.6) for patients who did not have an irAE compared to 37.8 months (IQR, 19.7–51.7) in those that did have an irAE and had further therapy reinitiated (HR, 0.38; p < 0.0001). The overall survival difference for patients with an irAE between the “ICI rechallenged” (37.8 months) and “ICI interrupted and not reinitiated (i.e., discontinued)” groups (24.9 months) was not found to be significantly significant (p = 0.7046).
In patients with ICI interrupted then reinitiated, the median duration of initial irAE was found to be a median of 2 months (IQR 1–4) and occurred sooner than ICI interrupted/discontinued and not reinitiated patients (median, 3.5 months; IQR 2–8; p = 0.0876) (Table 4). There were no statistical differences in the median observation period between the two groups. The grades of initial irAE were more serious in the non-reinitiated group (p < 0.001), having 80% with grades 3–4 irAEs vs. only 44% in the reinitiated group. Yet similar proportions of patients were found to have been treated with immunosuppression (87% in the reinitiated versus 86% in non-reinitiated, p = 0.50) between the two cohorts. The median overall survival was 38.6 months (IQR, 16.4-not reached) for patients who were reinitiated after irAE interrupted period compared to 24.9 months in those who were interrupted but not reinitiated on ICI (i.e., ICI discontinued) (IQR, 12.2-not reached, p = 0.2548). Figure 1 depicts the comparison in Kaplan–Meier survival analysis between these two cohorts.
A Cox multivariate proportional model (Table 5) analysis of the irAE positive patients demonstrates that the ICI “rechallenged post-interruption” cohort (interrupted and then reinitiated group) is not significantly associated with lower risk of death (HR = 1.19; CI 0.70–2.03; p = 0.52) compared to the ICI “not rechallenged” cohort (interrupted and non-reinitiated), adjusted for ICI duration of use. Patients treated with anti-PD-L1 ICI were associated with a higher risk of death (HR = 2.67, CI 1.19–6.00; p = 0.02). Being treated with anti-CTLA-4-based ICI regimen was associated with lower risk of death compared to anti-PD-1 (HR = 0.50, CI 0.26–0.94; p = 0.03). ECOG performance status and tumor locations were not significant covariates. Of note, the irAE grades were not found to be significant covariates. Supplemental Figure S1 shows the Kaplan–Meier survival analysis of ICI “interrupted and non-reinitiated” versus the “no irAEs” group (p < 0.0001).
4. Discussion
To our knowledge, this is one of the first real-world experience studies with long-term follow-up conducted at a single center that investigated the survival outcomes in patients with irAEs who were rechallenged with immunotherapy to treat solid or hematologic malignancies. In our current study, a Cox multivariate proportional analysis adjusted for time to events, found that among patients who developed irAEs and also with ICI therapy interrupted, those who subsequently had ICI therapy reinitiated did not have statistically significantly lower risk of death (HR, 1.19; p = 0.52) than patients who did not have ICI therapy reinitiated after interruption, despite a longer median ICI treatment duration in the former. These cohort groups were well balanced in demographics.
Our study also demonstrates that cancer patients who developed any irAEs and were rechallenged with ICI (with or without ICI treatment interruption) had significantly longer overall survival (HR, 0.34; p < 0.0001) than patients who did not develop irAEs. (Supplemental Table S2; Supplemental Figure S2) While there was a trend towards an increase in co-morbidities in the non-irAE group, the performance status was not different between these two groups. These findings corroborate well with the conclusions from several previous studies that focused on non-small cell lung cancer and melanoma [6,12]. Interestingly, a recent study has suggested a correlation between grade 3 or 4 immunotherapy related adverse events (irAEs) and the degree of durable response. Patients with advanced melanoma treated with ipilimumab who experienced grade 3 toxicities requiring steroids were found to have higher response rates to therapy and a longer median duration of response [13]. It was postulated by the investigators that these toxicities may reflect increased immunotherapy activity in melanoma, and thus as a result explaining the improved patient outcomes. Factors that predict irAEs, such as history of autoimmune disease, use of CTLA-4 inhibitors, and poor kidney function of grade 3 or higher, have been investigated and reported to date [3]. Within each malignancy, there can be found an abundance of intra-tumor heterogeneity and response/evolution to therapy [14]. This may explain the predominant findings that melanoma and lung cancer patients who developed irAE are the ones also appeared to have improved overall survival compared to patients who did not develop irAE. A recent multicenter study further identified that development of multisystem irAEs was associated with improved survival outcomes in patients with advanced NSCLC treated ICIs [15]. In this study with multivariate model analysis, patients with 1 irAE and multisystem irAEs showed incrementally improved overall survival (adjusted HR, 0.86; p = 0.26; and adjusted HR 0.57; p = 0.005, respectively) compared with patients with no irAEs. Emerging evidence from these studies lend a growing support to the notion that irAEs under ICI cancer immunotherapy may be reflective of the mechanism-based autoimmune or inflammatory reactions towards the ICI. Hence, it could be a manifestation of the host’s systemic immune response primed and activated under the ICI therapy, and thus could in turn be predictive of more favorable clinical outcomes, given that the irAEs are managed appropriately.
Hyperthyroidism and hypothyroidism were the most common irAE observed in our patient population. PD-1 inhibitors are generally believed to inhibit T cells at later stages of the immune response in peripheral tissues and may improve survival outcomes in patients undergoing ICI treatment [16,17]. Interestingly, multivariable analysis in our study suggested improved outcomes in patients who had either anti-CTLA-4 ICI alone or with combination anti-PD-1 ICI. Conversely, anti-PD-L1 ICI was associated with worsened outcomes compared to anti-PD-1 ICI and this finding is corroborated by the aforementioned meta-analysis of 19 randomized clinical trials [17]. In addition to a class effect, there is a growing belief that the microbiologic composition of a patient’s gastrointestinal flora is associated with irAE development [18]. Our study did not demonstrate a survival difference in patients who had antibiotic use within 30 days of ICI initiation compared with those who did not. However, there is growing literature that suggests antibiotic use in this period adversely affects survival, although we were unable to demonstrate this in our study [19].
In one multivariate analysis of a pooled cohort of patients, the use of baseline corticosteroids at >10 mg/day of prednisone or its equivalence was independently associated with worse PFS and OS [20]. However, ours and other studies in NSCLC did not find this same association [21]. With regards to immunotherapy pharmacokinetics, it is currently accepted that there is a reduction in clearance of these therapies over time. Immunotherapeutic plasma levels have been noted to increase over time [22]. Factors such as larger baseline tumor size, lower Eastern Cooperative Oncology Group performance status score, and higher tumor response to treatment may potentially be associated with this reduced clearance and subsequent improved patient outcomes [23]. The potential confounding variable of corticosteroid use prior to the course of immunotherapy may be dose independent. However, one study suggested that the discontinuation of such therapy before the first dose of anti-PD-1 inhibitor was administered led to patient outcomes similar to corticosteroid-naïve patients [23]. In vivo studies of T-cells in ICI therapy have shown that CTLA-4, but not PD-L1, blockade can partially prevent the inhibitory effects of corticosteroids on the immune system and may partially explain the class effect demonstrated above [24]. The use of steroids before ICI initiation was not associated with reduced OS in our current study.
The decision of whether to rechallenge upon an irAE is an important and practical dilemma of growing interest, with an emphasis and need to accomplish in a clinically safe manner [11,25]. A 27% recurrence rate of the initial irAE was observed in our study compared to 28.8% in a recent large cross-sectional cohort study [26]. Two of the more common recurrent irAEs were colitis and pneumonitis, similar to other large studies [26]. Our study did not demonstrate a statistically significant survival difference between the “interrupted and reinitiated” versus “interrupted and non-reinitiated” patients after at least one irAE occurrence on ICI (Figure 1, Table 5). Notably, Cox multivariate proportional analysis in our study did not identify the severity of irAE grades as significant covariates. In a recent multivariate analysis of anti-PD-1-induced irAEs and survival outcomes in advanced melanoma, development of grade ≥3 irAEs (HR, 0.29, p = 0.024) was significantly associated with longer OS [12]. We acknowledge that our study analysis finding above could possibly be a result of our relatively small cohort size limitation and resultant lack of power. Nonetheless, we note that our study cohorts sample size is quite comparable with the recent related studies in this important topic including multicenter and global cohort studies [12,15,27]. Moreover, our study results could have significant implication and impact on clinical practice in ICI management in the context of treatment decisions regarding ICI “rechallenge or not” especially after ICI interruption due to irAEs. The recent study by Naqash et al. demonstrated a negative impact of irAE-related treatment discontinuation on survival; however, the exploratory study focused only on the use of nivolumab in NSCLC 2nd or further lines of therapy [27]. Currently, effort is underway to extend our single center study into a multicenter collaborative study to increase the study cohort size for validation and a better powered analysis.
There are several limitations to our study. First, the study was conducted at a single institution in a state with generally higher medical comorbidities and reported cancer disparities compared to the rest of the country. Thus, generalizability to the general national population may be limited. Furthermore, there may be intrinsic cancer biology and molecular landscape differences in the tumors of Appalachian cancer patients due to unique geographic, social, cultural and epidemiologic variances of the population. Second, this is a retrospective study that has an expectant intrinsic selection bias. Third, the sample size was relatively modest and limited our ability to analyze subgroups within the irAE group. Although our cohort incorporated multiple cancer subtypes, multivariable analysis suggested that the survival benefit in the rechallenged group also applied to the largest cohort groups (lung, melanoma). Lastly, the decision to rechallenge with or without ICI discontinuation in the face of irAEs in this study was primarily clinician dependent, guided by individual clinical judgement and national guidelines (e.g., NCCN), and thus a potential confounding variable. Nonetheless, it also highlights the urgent need for further outcome research into the critical questions we posed in our study relating to the many levels of clinical dilemma and treatment decisions in the face of significant irAEs under ICI therapy, especially after treatment interruption.
5. Conclusions
Manifestation of irAEs onset is a common event under ICI cancer therapy; and appears to be a favorable predictive and prognostic marker based on emerging literature. Hence, it is a clinically relevant and pressing question whether patients should be rechallenged with ICI in the event of irAEs occurrence, with or without ICI treatment interruption, in order to maximize ICI clinical benefits. Here, our single center retrospective study findings identified no significant improvement in survival outcomes among the ICI-treated patients who developed irAEs, and resultant ICI therapy interruption followed by reinitiation, compared with those with ICI non-reinitiation. Hence reinitiation of ICI after irAEs-related treatment interruption may not correlate with improved survival outcomes and may not always be clinically warranted. Further research is urgently needed to explore the relationship between initiation of immunotherapy, subsequent immune-mediated toxicities within the inflammatory micro/macro-environment, extent of durable response in patients that respond to such therapies, and ultimately patient outcomes after ICI rechallenge in all malignancy types.
Acknowledgments
The authors acknowledge the support of Gerry Hobbs for his early support in the project. Patrick C. Ma is supported by the Frank and Franco Cancer Research Endowment, Penn State Cancer Institute.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/13/5/989/s1, Table S1: Type of irAEs after Initial ICI Reinitiation. Table S2: Cox multivariate proportional analysis irAE rechallenged vs. non-irAE. Figure S1: Kaplan-Meier Survival Analysis of Study Patients with No irAEs (blue) compared with those ICI “Interrupted and Not Reinitiated (i.e., Discontinued)” (red). Figure S2: Kaplan-Meier Survival Analysis of the Study Patients with No irAEs (blue) compared with the “ICI Rechallenged” Cohort (ICI Reinitiated +/− Interruption) after irAEs.
Click here for additional data file.
Author Contributions
Conceptual design: H.J.A., P.C.M.; data compilation: J.F., S.S., H.J.A.; manuscript write-up: H.J.A., S.A.M., P.C.M.; statistical analysis: J.M.A. All authors have read and agreed to the published version of the manuscript.
Funding
There was no financial support for this research study. This work has not been submitted or presented elsewhere.
Institutional Review Board Statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of West Virginia University (Protocol number 1908667775, approved 16 July 2019).
Informed Consent Statement
Patient consent was waived due to the research involved no more than minimal risk to subjects and the research could not be carried out practicably without the waiver.
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPAA concerns.
Conflicts of Interest
Dr. Patrick C. Ma declares the potential conflicts of interest as: speakers’ bureau in Merck, AstraZeneca and Bristol-Myers Squibb; and ad hoc consulting with AstraZeneca. The other authors declare no conflict of interest.
Declarations
This manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest and accurate work worthy of publication. There are no competing interests to this manuscript. All authors had access to the data and material.
Abbreviations
irAE immune related adverse event
ICI immune checkpoint inhibitor
mOS median overall survival
PD-1 programmed death 1
PD-L1 programmed death-ligand 1
CTLA-4 cytotoxic T-lymphocyte –associated protein 4
CNS central nervous system
RECIST Response Evaluation Criteria In Solid Tumors
CTCAE Common Terminology Criteria for Adverse Events
TPS tumor proportion score
NCCN National Comprehensive Cancer Network
Figure 1 Kaplan-Meier Survival Analysis of Study Patients with ICI irAEs Having ICI Interrupted and Not Reinitiated (i.e., Discontinued) (blue) versus Interrupted and Reinitiated (red).
cancers-13-00989-t001_Table 1 Table 1 General Characteristics of the Study Patients who had ICI Treatment With and Without irAE.
Characteristics Patients, No. (%)
Patients with irAE
(N = 133) Patients without irAE
(N = 131) p
Median age, years (IQR) 65 (59–73) 63 (55–69) 0.07
Male Sex 71 (53) 80 (61) 0.21
Caucasian 131 (99) 124 (95) 0.13
Comorbid conditions present 91 (68) 106 (81) 0.08
ECOG Performance Status
0–1 108 (81) 101 (77) 0.45
2–3 25 (19) 30 (23) 0.44
Tumor Grade
Poorly differentiated 66 (50) 78 (60) 0.10
Cancer Stage N = 114 N = 118
III 27 (20) 28 (21) 0.83
IV 87 (65) 90 (69) 0.57
Cancer Type
Lung 53 (40) 59 (45) 0.39
Melanoma 39 (29) 25 (19) 0.04
Genitourinary 14 (11) 13 (10) 0.87
Other solid * 9 (1) 4 (3) 0.57
Hematologic ** 3 (2) 4 (3) 0.61
CNS disease present 35 (26) 42 (32) 0.30
Steroids required for CNS disease 31 (89) 34 (76) 0.51
Median observation period, months (IQR) 14.5 (6–25) 13.3 (4–23)
Initial Immunotherapy
Anti-PD-1 87 (65) 109 (83) 0.45
Anti-CTLA-4 10 (8) 9 (7) 0.84
Combination anti-PD-1/CTLA-4 20 (15) 1 (1) <0.001
Anti-PD-L1 16 (12) 12 (9) 0.05
Steroid use within 30 days of ICI initiation 33 (25) 28 (21) 0.51
Antibiotic use within 30 days of ICI initiation 31 (23) 27 (21) 0.60
PD-L1 Status (% TPS) N = 65 N = 57
≥50 21 (32) 12 (21) 0.04
1–49 19 (29) 24 (42) 0.03
<1 25 (38) 21 (37) 0.9
Abbreviations: ECOG, eastern cooperative oncology group; CNS, central nervous system; IQR, interquartile range; ICI, immune checkpoint inhibitor; irAE, immune related adverse event; PD-1/L1, programmed cell death-1 or ligand 1; CTLA-4, cytotoxic T-cell lymphocyte-4; * Other solid types include: duodenal, breast, head and neck, adrenal cortical carcinoma, esophageal, colon, ovarian, gastric, merkel cell, endometrial, and cervical cancer. PD-L1 status was measured by tumor proportion score (TPS, %). ** Hematologic malignancies include: Hodgkin’s lymphoma, mycosis fungoides, and diffuse large B cell lymphoma.
cancers-13-00989-t002_Table 2 Table 2 Characteristics of Initial and Sequential irAEs.
irAE (n = 133) Patients, No. (%)
Hypothyroidism 43 (32)
Rash 30 (23)
Diarrhea/colitis 22 (17)
Pneumonitis 17 (13)
Adrenal Insufficiency 12 (9)
Hepatitis 9 (7)
Nephritis 6 (5)
Hypophysitis 3 (2)
Diabetes mellitus 3 (2)
Myalgia 3 (2)
Encephalopathy 2 (2)
Other ** 8 (6)
Grade of irAE (n = 115)
2 70 (61)
3–4 45 (39)
Immunotherapy rechallenged after irAE 98 (74)
Immunotherapy interrupted (with or without subsequent reinitiation) after irAE 74 (56)
Identical Immunotherapy used after irAE (n = 98) 83 (85)
Immunotherapy used after irAE (n = 98)
Anti-PD-1 79 (81)
Anti-CTLA-4 2 (2)
Combination anti-PD-1/CTLA-4 5 (5)
Anti-PD-L1 12 (12)
Median duration of ICI therapy after irAE, cycles (IQR) 7 (3–14.75)
Median duration from irAE to ICI resumption, days (IQR, n = 38) 28 (16–44)
Median duration from ICI resumption to 2nd irAE, months (IQR, n = 38) 3 (1–6)
Median duration from ICI resumption to 3rd irAE, months (IQR, n = 7) 10 (6–18)
New IrAE after reinitiation of Immunotherapy (n = 98) 41 (42)
Grade of second irAE (n = 41)
1–2 29 (71)
3–4 12 (29)
IrAE after ICI interruption and reinitiated rechallenge the same as first irAE 11 (27)
IrAE after second interruption and reinitiated rechallenge (n = 7) the same as first irAE 4 (57)
Grade of irAE after second reinitiation (n = 7)
1–2 4 (57)
3 3 (43)
Need for Immunosuppression 80 (60)
PO/IV Steroids 63 (79)
TNF-alpha inhibition 3 (<1)
Topical steroids 14 (18)
** Other irAE included arthralgia, MAHA, uveitis, SIADH, aseptic meningitis.
cancers-13-00989-t003_Table 3 Table 3 “Rechallenged (Interrupted and Reinitiated + Not interrupted and Reinitiated after irAE)” compared to “Discontinued and Not Reinitiated”.
Characteristics ICI Rechallenged Patients, No. (%) ICI Discontinued and Not Reinitiated Patients, No. (%) p
No. of patients 98 35
Age, IQR 64 (58.25–72) 68 (60–74) 0.10
Alcohol status
Current 27 (28) 6 (17) 0.56
Former 32 (33) 15 (43)
Smoking status
Current 16 (16) 7 (20) 0.28
Former 53 (54) 22 (63)
Never 29 (30) 6 (17)
Comorbid conditions present 71 (72) 20 (57) 0.10
ECOG Performance Status
0–1 84 (86) 29 (83) 0.75
2–3 14 (14) 6 (17)
Median observed period, days 434.5 (173.5–771.5) 446 (222–707) 0.81
Median duration of ICI therapy, months (IQR) 10 (4–17) 3 (1–6) <0.0001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.02
Initial Immunotherapy
Anti-PD-1 65 (66) 22 (63) 0.97
Anti-CTLA-4 7 (7) 3 (9)
Combination anti-PD-1/CTLA-4 15 (15) 5 (14)
Anti-PD-L1 11 (11) 5 (14)
Steroid use within 30 days of ICI initiation 23 (23) 10 (29) 0.98
Antibiotic use within 30 days of ICI initiation 24 (24) 7 (20) 0.26
CNS disease present 26 (27) 9 (26) 0.82
Steroids used for CNS disease 23 (23) 8 (23) 0.98
PD-L1 Status (% TPS) 48 17
≥50 15 (31) 6 (35) 0.32
1–49 15 (31) 4 (11)
<1 18 (38) 7 (20)
Grade of irAE
2 63 (64) 7 (20) <0.0001
3–4 17 (17) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 3 (2–6) 4 (3–8.5) 0.03
Need for Immunosuppression 50 (51) 30 (86) <0.0001
PO/IV Steroids 34 (67) 29 (97)
TNF-alpha inhibition 2 (4) 1 (3)
Topical steroids 14 (28) 0 (0)
Disease status after completion of ICI 96 33
Complete response 27 (28) 10 (30) 0.80
Partial response 10 (10) 2 (6)
Stable disease 17 (18) 8 (24)
Progression of disease 42 (44) 13 (39)
mOS, months (IQR) 37.8 (19.7–51.7) 24.9 (12.2-NR) 0.7046
cancers-13-00989-t004_Table 4 Table 4 Characteristics of Patients with IrAE and Stratified by ICI Interrupted Status.
Characteristics ICI Interrupted, then Reinitiated Patients, No. (%) ICI Interrupted and Not Reinitiated (i.e., Discontinued) Patients, No. (%) p
No. of patients 39 35
Age, IQR 64 (59–71.5) 68 (60–74) 0.91
Alcohol status
Current 10 (26) 6 (17) 0.52
Former 11 (28) 15 (43)
Smoking status
Current 7 (18) 7 (20) 0.60
Former 22 (56) 22 (63)
Never 10 (26) 6 (17)
Comorbid conditions present 27 (69) 20 (57)
ECOG Performance status
0–1 35 (90) 29 (83) 0.44
2–3 4 (10) 6 (17)
Median observed period, months (IQR) 16 (11–31) 15 (7–24) 0.38
Median duration of total ICI therapy, months (IQR) 12 (4–21.5) 3 (1–8) <0.001
Median duration between initial ICI therapy and initial irAE, months (IQR) 2 (1–4) 3.5 (2–8) 0.09
Initial Immunotherapy
Anti-PD-1 20 (51) 22 (63) 0.75
Anti-CTLA-4 5 (13) 3 (9)
Combination anti-PD-1/CTLA-4 8 (21) 5 (14)
Anti-PD-L1 6 (15) 5 (14) 0.58
Steroid use within 30 days of ICI initiation 8 (21) 10 (29) 0.90
Antibiotic use within 30 days of ICI initiation 11 (28) 7 (20) 0.13
CNS disease present 15 (38) 9 (26) 0.40
Steroids used for CNS disease 13 (33) 8 (23) 0.68
PD-L1 Status n = 48 n = 17
≥50 6 (15) 6 (35) 0.58
1–49 6 (15) 4 (11)
<1 8 (21) 7 (20)
Grade of irAE
2 19 (49) 7 (20) <0.001
3–4 17 (44) 28 (80)
Median duration of ICI therapy prior to irAE, cycles (IQR) 4 (2–6) 4 (3–8.5)
Need for Immunosuppression for irAE n = 34 (87) N = 30 (86) 0.50
PO/IV Steroids 28 (82) 29 (97)
TNF-alpha inhibition 2 (6) 1 (3)
Topical steroids 4 (12) 0 (0)
Disease status after completion of ICI 39 33
Complete response 11 (31) 10 (30)
Partial response 5 (14) 2 (6)
Stable disease 8 (22) 8 (24)
Progression of disease 15 (33) 13 (39)
mOS, months (IQR) 38.6 (16.4-NR) 24.9 (12.2-NR) 0.2548
cancers-13-00989-t005_Table 5 Table 5 Cox multivariate proportional model depicting the risk of overall survival in groups of ICI reinitiation status adjusting for the effect of covariates.
Effect Categories Hazard Ratio * Lower CI Upper CI p
Group IrAE and not rechallenged (interrupted + non-reinitiated) Ref
IrAE and rechallenged post-interruption (interrupted + reinitiated) 1.19 0.70 2.03 0.52
Age ≤60Y Ref
>60Y 1.59 0.90 2.79 0.11
Gender Male Ref
Female 0.67 0.39 1.13 0.13
Immunotherapy type Pembro/Nivo (PD-1) Ref
Ipi & Ipi/Nivo (CTLA-4/PD-1) 0.50 0.26 0.94 0.05
Atezo/Durva/Avelu (PD-L1) 2.67 1.19 6.00 0.01
Antibiotic use No Ref
Yes 1.40 0.78 2.49 0.13
IrAE Grade 1–2 Ref
3–4 0.93 0.50 1.73 0.83
Median ICI duration, months 0.96 0.94 0.98 0.001
* Ref: Reference for hazard ratio analysis and comparison.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33673446 | 19,761,769 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Spontaneous resolution of atopic dermatitis incidental to participation in benralizumab clinical trial for severe, uncontrolled asthma: a case report.
BACKGROUND
T cell-mediated eosinophilia is associated with numerous conditions-including atopic dermatitis, food allergies, and asthma-collectively known as the "atopic march." Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody directed against the ⍺ chain of the eosinophil cell surface receptor IL-5R. Benralizumab treatment causes near-complete depletion of circulating eosinophils and was approved in 2017 for add-on, maintenance treatment of severe asthma with an eosinophilic phenotype, based on the results of the CALIMA and SIROCCO pivotal trials. Benralizumab is not currently approved for the treatment of eosinophilic conditions besides asthma; however, during the CALIMA trial, spontaneous resolution of atopic dermatitis was observed in a patient, concurrent with reduction in her asthma symptoms.
METHODS
In January 2015, a 14-year-old Asian girl with severe, uncontrolled asthma was enrolled in CALIMA. The patient's baseline eosinophil blood count was 1200 cells/μL, her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9 and her asthma exacerbation rate in the prior year was 4. She also displayed a pronounced, pruritic, chronic, inflammatory rash consistent with atopic dermatitis across her face. The investigator was blinded to the patient's treatment group during treatment; however, her asthma symptoms diminished over the course of the study (FEV1 at 56 weeks, 3.01 L/110.5% (pre) and 3.25 L/119.3% (post); overall asthma symptom score 2.1; one influenza-associated exacerbation). Furthermore, her atopic dermatitis symptoms resolved spontaneously within the first 5 months of the study. After unblinding, the patient was confirmed to have been randomized to an active treatment arm, and her blood eosinophil count had dropped below the limit of detection after the first study dose.
CONCLUSIONS
Given the potential shared mechanisms between eosinophilic asthma and atopic dermatitis, it is plausible that benralizumab-induced eosinopenia factored into the resolution of the patient's atopic dermatitis. Further clinical studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be useful in managing multiple conditions associated with eosinophilia.
Background
Eczema, or atopic dermatitis (AD), is a chronic, pruritic, inflammatory skin condition with a mechanism linked to deficiency of function in the skin barrier [1, 2]. Challenge by environmental allergens and pathogenic microbes precipitates a complex and exaggerated pro-inflammatory T cell response that includes interleukin-5 (IL-5) stimulation of eosinophil proliferation, activation, and subsequent overproduction of immunoglobulin E (IgE) [1, 2]. AD tends to precede or co-occur with other allergic diseases such as food allergies, severe eosinophilic asthma, and allergic rhinitis. It is increasingly understood that the physiologic mechanisms underlying these disorders overlap and may be part of a pathologic cascade [3].
The potential links between these allergic diseases point to a number of attractive therapeutic targets, including IgE antibodies, IL-5, and eosinophils, which are stimulated through the cell surface receptor, IL-5R [4–6]. Several pharmaceutical agents have been approved or are currently in development that are designed to disrupt the IL-5/IL-5R interaction in eosinophilic asthma, AD, or other allergic diseases [4]. However, it is not yet known whether agents developed against one indication will show efficacy against others within the constellation of atopic diseases.
Here, we report spontaneous resolution of AD in an adolescent patient participating in the phase 3 CALIMA pivotal trial, which evaluated the safety and efficacy of the anti-IL-5R mAb benralizumab as an add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts [7].
Case presentation
In December 2013, a 14-year-old Asian girl (body mass index 22.34; never-smoker) was referred to our practice with severe, uncontrolled asthma, which was first diagnosed in 2009. At the time of referral, the patient was taking budesonide 160 μg and formoterol 4.5 μg, two puffs twice daily plus formoterol 18 μg daily. Her history was also significant for allergic rhinitis, AD, and IgE-confirmed allergies to an extensive panel of foods and to animal dander.
Her medications were adjusted to budesonide 160 μg and formoterol 4.5 μg taken as two puffs twice-daily, montelukast 5 mg daily, and salbutamol as needed; however, this regimen did not achieve satisfactory symptom control. In December 2014 she was screened for potential enrollment into the CALIMA clinical trial [7].
At the enrollment visit in January 2015, the patient’s eosinophil blood count was 1200 cells/μL. Her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9. She had experienced four asthma exacerbations requiring treatment with systemic corticosteroids in the year prior to enrollment. Furthermore, a pronounced, pruritic, inflammatory rash consistent with AD was evident on the patient’s cheeks and forehead (Fig. 1, left panel). The patient and her guardian confirmed that the rash was chronic, and it was documented photographically as part of the patient record. Following completion of pre-enrollment screening and informed consent from her guardian, the patient was enrolled in the study and underwent the specified 4-week screening and run-in period [7]. She met all selection criteria and was randomized to blinded treatment assignment in January 2015. The patient completed a study visit every 4 weeks for 56 weeks for data collection and subcutaneous injection of her assigned study drug, and attended the 60-week final study visit. The patient was 100% compliant with the schedule and all study procedures. During the study, the patient continued using her background asthma controller medications, and was allowed to use albuterol two puffs, four times per day as needed as her rescue medication.Fig. 1 Progressive resolution of eczematous lesions in a patient participating in the CALIMA randomized clinical trial evaluating benralizumab as an add-on treatment for severe asthma with eosinophilic phenotype. The pictures were taken on the basis of clinical observation and without knowledge of the patient’s assigned dose group. After the trial was completed and unblinded, the patient was found to be in the treatment arm that received benralizumab 30 mg every 8 weeks, with the first three doses every 4 weeks, and in the primary analysis population of patients with at least 300 eosinophils/μL peripheral blood
As CALIMA was a randomized, double-blind, placebo-controlled, parallel-group trial [7], it was not known to which arm the patient had been randomized and her eosinophil counts were redacted during the study and were unknown to the investigator or patient. However, during the course of treatment, the patient noted fewer asthma symptoms and reduced dyspnea during activities. Furthermore, a consistent and progressive resolution of her AD symptoms was observed and documented over 5 months (Fig. 1, middle and right panels). She experienced a single exacerbation requiring systemic corticosteroid treatment on day 363 of the study (December 2015), coincident with an influenza infection.
After the study was completed and unblinded, the patient was confirmed to have received 30 mg benralizumab every 8 weeks over the course of the 56-week treatment period, with the first three doses administered 4 weeks apart (the “Q8W” study arm). Her data were confirmed to have been included in the primary (intention-to-treat) analysis of patients with eosinophil count of at least 300 cells/μL.
At her 56-week study visit, the patient’s pre-bronchodilator FEV1 was 3.01 L (FEV1/FVC 110.5%), whereas her post-bronchodilator FEV1 was 3.3 L (FEV1/FVC 119.3%). Therefore, during the course of the study she gained 1.1 L in pre-bronchodilator FEV1. Furthermore, the patient’s overall asthma symptom score at 56 weeks was 2.1, a decrease of 1.8 points compared to baseline. For reference, in the CALIMA placebo group (n = 248), the least-squares mean change in pre-bronchodilator FEV1 was a 0.22-L increase, and the least-squares mean change in asthma symptom score was − 1.2 [7].
Furthermore, the patient’s blood eosinophil count dropped below the limit of detection by the 4-week visit (after one study dose) and remained there throughout the 56-week duration of the study.
Discussion and conclusions
This case is notable in that the patient was enrolled in a clinical trial focused on a specific drug indication—severe, uncontrolled asthma with elevated blood eosinophil counts—but experienced dramatic resolution of symptoms for a different condition that may have a related mechanism of action. Evidence is increasing that the pathology of asthma, AD, and other diseases that are part of the so-called atopic march are a result of a self-reinforcing and progressive cascade of epithelial barrier dysfunction in the skin, gut mucosa, and respiratory mucosa, allowing increased penetration of allergens and microbes that elicit a systemic, T cell-mediated eosinophilic hyper-response [2, 3, 8]. Because this inappropriate eosinophilic response is characteristic of all of the atopic diseases, it is conceivable that treatments targeting the underlying T cell–eosinophil interaction could potentially show efficacy against more than one condition [2–6]. However this hypothesis must be investigated for each combination of drug and condition and the therapies currently on the market are, so far, limited to single indications.
Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody (mAb) directed against the ⍺ chain of IL-5R, a receptor that is abundant on the surface of eosinophils and basophils and is essential to their function and survival [9, 10]. The engineered afucosylation enhances the receptor binding affinity of benralizumab as well as its antibody-dependent cell-mediated cytotoxicity function [9], resulting in near-total depletion of eosinophils from the circulation, and from the airways and lungs, and approximately 80% depletion of eosinophilic progenitors from the bone marrow [10, 11].
CALIMA was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 clinical trial conducted at 303 sites in 11 countries [7]. Patients enrolled in the study were aged 12–75 years with severe asthma uncontrolled by medium- to high-dose inhaled corticosteroids (ICS) with long-acting β2-agonists (LABA) and a history of two or more exacerbations in the previous year. Patients were randomized in a 1:1:1 ratio to receive 56 weeks of treatment with benralizumab 30 mg subcutaneous every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo. The study population was also stratified (2:1) by baseline blood eosinophil counts (at least 300 cells/μL versus less than 300 cells/μL). The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dose ICS plus LABA with baseline blood eosinophils at least 300 cells/μL (intent-to-treat analysis). Secondary endpoints were FEV1 and total asthma symptom score.
Of 2505 patients enrolled and 1306 randomized, 728 patients were included in the primary analysis population. The study found that 56 weeks of add-on therapy with benralizumab at either dose level reduced annual exacerbation rates in patients with severe asthma and elevated baseline blood eosinophil counts by up to 36% compared with placebo (Q4W rate ratio 0.64 [95% CI 0.49–0.85], p = 0.0018, n = 241; and Q8W rate ratio 0.72 [95% CI 0.54–0.95], p = 0.0188, n = 239). Benralizumab also significantly improved pre-bronchodilator FEV1 in the Q4W and Q8W groups, and total asthma symptom score in the Q8W group. Furthermore, patients in both active dose groups experienced near-complete depletion of blood eosinophils by the 4-week sampling time point. The drug was well tolerated with few drug-related adverse events.
On the basis of the results of CALIMA and another pivotal trial, SIROCCO [7, 12], benralizumab was approved in 2017 by the US Food and Drug Administration as Fasenra® for add-on maintenance treatment of patients with severe asthma, aged 12 years and older, with an eosinophilic phenotype [13]. The medication is not approved for treatment of other eosinophilic conditions and is not for relief of acute bronchospasm or status asthmaticus. Results from the first year of a long-term safety study (the BORA phase 3 extension trial) are consistent with efficacy and safety outcomes from the pivotal trials [14]. To date, benralizumab has not been evaluated clinically for its efficacy against AD, although a phase 2 study is being planned to further characterize its potential therapeutic role.
The asthma symptoms of the patient in this case responded to benralizumab in a manner consistent with the aggregate responses in patients in the Q8W arm of the CALIMA trial, with a reduced 56-week exacerbation rate, improved lung function, reduced asthma symptom score, and near-total depletion of blood eosinophils. The observed reduction in AD symptoms occurred concurrent with that response, as is evident in Fig. 1, with a substantial decrease in inflammation at 2 months compared with baseline, and skin healing at 5 months. It is noteworthy that the improvements in the patient’s AD symptoms occurred in the absence of any systemic steroid use for asthma exacerbation; the patient received systemic steroids only once during the study period, on day 363.
It is important to acknowledge that the findings reported here were incidental, observed during a case that was part of a large prospective clinical trial. A post hoc attempt to identify other patients in the study with similar findings would be practically infeasible and limited by unavoidable selection bias. However, the strength of the observed effect in this case suggests a potential area for investigation.
In conclusion, we observed spontaneous resolution of AD coincident with participation in a clinical trial for benralizumab to treat severe, uncontrolled, eosinophilic asthma. Given the plausible overlap in pathologic mechanisms between asthma and AD, further studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be efficacious in managing multiple allergic diseases.
Abbreviations
ACQ-6 Asthma Control Questionnaire-6
AD Atopic dermatitis
FEV1 Forced expiratory volume in 1 second
ICS Inhaled corticosteroids
IgE Immunoglobulin E
IL-5/IL-5R Interleukin-5/interleukin-5 receptor
LABA Long-acting β2-agonist
mAb Monoclonal antibody
Q4W CALIMA study group: benralizumab 30 mg every 4 weeks
Q8W CALIMA study group: benralizumab 30 mg every 8 weeks, first three doses 4 weeks apart
Acknowledgements
Jeanne McAdara PhD and Citrus Healthcare Communications Group provided professional medical writing assistance, which was funded by AstraZeneca.
Author’s information
Dr. Pham’s career in medical research and practice has focused on studying mechanisms in T cell development and T cell-mediated immune and allergy responses. He attended medical school at the University of Maryland, completed an immunology research fellowship at the National Institute of Allergy and Infectious Diseases, a residency in internal medicine at Tulane University, and another fellowship in pulmonary critical care research and medicine at the University of Colorado and National Jewish Health.
Authors' contributions
As the sole author, DNP collected patient data, oversaw drafting of the manuscript, provided critical review, and approved the manuscript for submission. The author read and approved the final manuscript.
Funding
AstraZeneca provided funding for professional medical writing assistance.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The patient’s legal guardian gave informed consent for the patient to participate in the CALIMA clinical trial.
Consent for publication
Written informed consent was obtained from the patient and her legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
DNP declares that he has no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALBUTEROL, BUDESONIDE\FORMOTEROL, MONTELUKAST SODIUM | DrugsGivenReaction | CC BY | 33673870 | 19,120,052 | 2021-03-06 |
What was the dosage of drug 'ALBUTEROL'? | Spontaneous resolution of atopic dermatitis incidental to participation in benralizumab clinical trial for severe, uncontrolled asthma: a case report.
BACKGROUND
T cell-mediated eosinophilia is associated with numerous conditions-including atopic dermatitis, food allergies, and asthma-collectively known as the "atopic march." Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody directed against the ⍺ chain of the eosinophil cell surface receptor IL-5R. Benralizumab treatment causes near-complete depletion of circulating eosinophils and was approved in 2017 for add-on, maintenance treatment of severe asthma with an eosinophilic phenotype, based on the results of the CALIMA and SIROCCO pivotal trials. Benralizumab is not currently approved for the treatment of eosinophilic conditions besides asthma; however, during the CALIMA trial, spontaneous resolution of atopic dermatitis was observed in a patient, concurrent with reduction in her asthma symptoms.
METHODS
In January 2015, a 14-year-old Asian girl with severe, uncontrolled asthma was enrolled in CALIMA. The patient's baseline eosinophil blood count was 1200 cells/μL, her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9 and her asthma exacerbation rate in the prior year was 4. She also displayed a pronounced, pruritic, chronic, inflammatory rash consistent with atopic dermatitis across her face. The investigator was blinded to the patient's treatment group during treatment; however, her asthma symptoms diminished over the course of the study (FEV1 at 56 weeks, 3.01 L/110.5% (pre) and 3.25 L/119.3% (post); overall asthma symptom score 2.1; one influenza-associated exacerbation). Furthermore, her atopic dermatitis symptoms resolved spontaneously within the first 5 months of the study. After unblinding, the patient was confirmed to have been randomized to an active treatment arm, and her blood eosinophil count had dropped below the limit of detection after the first study dose.
CONCLUSIONS
Given the potential shared mechanisms between eosinophilic asthma and atopic dermatitis, it is plausible that benralizumab-induced eosinopenia factored into the resolution of the patient's atopic dermatitis. Further clinical studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be useful in managing multiple conditions associated with eosinophilia.
Background
Eczema, or atopic dermatitis (AD), is a chronic, pruritic, inflammatory skin condition with a mechanism linked to deficiency of function in the skin barrier [1, 2]. Challenge by environmental allergens and pathogenic microbes precipitates a complex and exaggerated pro-inflammatory T cell response that includes interleukin-5 (IL-5) stimulation of eosinophil proliferation, activation, and subsequent overproduction of immunoglobulin E (IgE) [1, 2]. AD tends to precede or co-occur with other allergic diseases such as food allergies, severe eosinophilic asthma, and allergic rhinitis. It is increasingly understood that the physiologic mechanisms underlying these disorders overlap and may be part of a pathologic cascade [3].
The potential links between these allergic diseases point to a number of attractive therapeutic targets, including IgE antibodies, IL-5, and eosinophils, which are stimulated through the cell surface receptor, IL-5R [4–6]. Several pharmaceutical agents have been approved or are currently in development that are designed to disrupt the IL-5/IL-5R interaction in eosinophilic asthma, AD, or other allergic diseases [4]. However, it is not yet known whether agents developed against one indication will show efficacy against others within the constellation of atopic diseases.
Here, we report spontaneous resolution of AD in an adolescent patient participating in the phase 3 CALIMA pivotal trial, which evaluated the safety and efficacy of the anti-IL-5R mAb benralizumab as an add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts [7].
Case presentation
In December 2013, a 14-year-old Asian girl (body mass index 22.34; never-smoker) was referred to our practice with severe, uncontrolled asthma, which was first diagnosed in 2009. At the time of referral, the patient was taking budesonide 160 μg and formoterol 4.5 μg, two puffs twice daily plus formoterol 18 μg daily. Her history was also significant for allergic rhinitis, AD, and IgE-confirmed allergies to an extensive panel of foods and to animal dander.
Her medications were adjusted to budesonide 160 μg and formoterol 4.5 μg taken as two puffs twice-daily, montelukast 5 mg daily, and salbutamol as needed; however, this regimen did not achieve satisfactory symptom control. In December 2014 she was screened for potential enrollment into the CALIMA clinical trial [7].
At the enrollment visit in January 2015, the patient’s eosinophil blood count was 1200 cells/μL. Her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9. She had experienced four asthma exacerbations requiring treatment with systemic corticosteroids in the year prior to enrollment. Furthermore, a pronounced, pruritic, inflammatory rash consistent with AD was evident on the patient’s cheeks and forehead (Fig. 1, left panel). The patient and her guardian confirmed that the rash was chronic, and it was documented photographically as part of the patient record. Following completion of pre-enrollment screening and informed consent from her guardian, the patient was enrolled in the study and underwent the specified 4-week screening and run-in period [7]. She met all selection criteria and was randomized to blinded treatment assignment in January 2015. The patient completed a study visit every 4 weeks for 56 weeks for data collection and subcutaneous injection of her assigned study drug, and attended the 60-week final study visit. The patient was 100% compliant with the schedule and all study procedures. During the study, the patient continued using her background asthma controller medications, and was allowed to use albuterol two puffs, four times per day as needed as her rescue medication.Fig. 1 Progressive resolution of eczematous lesions in a patient participating in the CALIMA randomized clinical trial evaluating benralizumab as an add-on treatment for severe asthma with eosinophilic phenotype. The pictures were taken on the basis of clinical observation and without knowledge of the patient’s assigned dose group. After the trial was completed and unblinded, the patient was found to be in the treatment arm that received benralizumab 30 mg every 8 weeks, with the first three doses every 4 weeks, and in the primary analysis population of patients with at least 300 eosinophils/μL peripheral blood
As CALIMA was a randomized, double-blind, placebo-controlled, parallel-group trial [7], it was not known to which arm the patient had been randomized and her eosinophil counts were redacted during the study and were unknown to the investigator or patient. However, during the course of treatment, the patient noted fewer asthma symptoms and reduced dyspnea during activities. Furthermore, a consistent and progressive resolution of her AD symptoms was observed and documented over 5 months (Fig. 1, middle and right panels). She experienced a single exacerbation requiring systemic corticosteroid treatment on day 363 of the study (December 2015), coincident with an influenza infection.
After the study was completed and unblinded, the patient was confirmed to have received 30 mg benralizumab every 8 weeks over the course of the 56-week treatment period, with the first three doses administered 4 weeks apart (the “Q8W” study arm). Her data were confirmed to have been included in the primary (intention-to-treat) analysis of patients with eosinophil count of at least 300 cells/μL.
At her 56-week study visit, the patient’s pre-bronchodilator FEV1 was 3.01 L (FEV1/FVC 110.5%), whereas her post-bronchodilator FEV1 was 3.3 L (FEV1/FVC 119.3%). Therefore, during the course of the study she gained 1.1 L in pre-bronchodilator FEV1. Furthermore, the patient’s overall asthma symptom score at 56 weeks was 2.1, a decrease of 1.8 points compared to baseline. For reference, in the CALIMA placebo group (n = 248), the least-squares mean change in pre-bronchodilator FEV1 was a 0.22-L increase, and the least-squares mean change in asthma symptom score was − 1.2 [7].
Furthermore, the patient’s blood eosinophil count dropped below the limit of detection by the 4-week visit (after one study dose) and remained there throughout the 56-week duration of the study.
Discussion and conclusions
This case is notable in that the patient was enrolled in a clinical trial focused on a specific drug indication—severe, uncontrolled asthma with elevated blood eosinophil counts—but experienced dramatic resolution of symptoms for a different condition that may have a related mechanism of action. Evidence is increasing that the pathology of asthma, AD, and other diseases that are part of the so-called atopic march are a result of a self-reinforcing and progressive cascade of epithelial barrier dysfunction in the skin, gut mucosa, and respiratory mucosa, allowing increased penetration of allergens and microbes that elicit a systemic, T cell-mediated eosinophilic hyper-response [2, 3, 8]. Because this inappropriate eosinophilic response is characteristic of all of the atopic diseases, it is conceivable that treatments targeting the underlying T cell–eosinophil interaction could potentially show efficacy against more than one condition [2–6]. However this hypothesis must be investigated for each combination of drug and condition and the therapies currently on the market are, so far, limited to single indications.
Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody (mAb) directed against the ⍺ chain of IL-5R, a receptor that is abundant on the surface of eosinophils and basophils and is essential to their function and survival [9, 10]. The engineered afucosylation enhances the receptor binding affinity of benralizumab as well as its antibody-dependent cell-mediated cytotoxicity function [9], resulting in near-total depletion of eosinophils from the circulation, and from the airways and lungs, and approximately 80% depletion of eosinophilic progenitors from the bone marrow [10, 11].
CALIMA was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 clinical trial conducted at 303 sites in 11 countries [7]. Patients enrolled in the study were aged 12–75 years with severe asthma uncontrolled by medium- to high-dose inhaled corticosteroids (ICS) with long-acting β2-agonists (LABA) and a history of two or more exacerbations in the previous year. Patients were randomized in a 1:1:1 ratio to receive 56 weeks of treatment with benralizumab 30 mg subcutaneous every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo. The study population was also stratified (2:1) by baseline blood eosinophil counts (at least 300 cells/μL versus less than 300 cells/μL). The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dose ICS plus LABA with baseline blood eosinophils at least 300 cells/μL (intent-to-treat analysis). Secondary endpoints were FEV1 and total asthma symptom score.
Of 2505 patients enrolled and 1306 randomized, 728 patients were included in the primary analysis population. The study found that 56 weeks of add-on therapy with benralizumab at either dose level reduced annual exacerbation rates in patients with severe asthma and elevated baseline blood eosinophil counts by up to 36% compared with placebo (Q4W rate ratio 0.64 [95% CI 0.49–0.85], p = 0.0018, n = 241; and Q8W rate ratio 0.72 [95% CI 0.54–0.95], p = 0.0188, n = 239). Benralizumab also significantly improved pre-bronchodilator FEV1 in the Q4W and Q8W groups, and total asthma symptom score in the Q8W group. Furthermore, patients in both active dose groups experienced near-complete depletion of blood eosinophils by the 4-week sampling time point. The drug was well tolerated with few drug-related adverse events.
On the basis of the results of CALIMA and another pivotal trial, SIROCCO [7, 12], benralizumab was approved in 2017 by the US Food and Drug Administration as Fasenra® for add-on maintenance treatment of patients with severe asthma, aged 12 years and older, with an eosinophilic phenotype [13]. The medication is not approved for treatment of other eosinophilic conditions and is not for relief of acute bronchospasm or status asthmaticus. Results from the first year of a long-term safety study (the BORA phase 3 extension trial) are consistent with efficacy and safety outcomes from the pivotal trials [14]. To date, benralizumab has not been evaluated clinically for its efficacy against AD, although a phase 2 study is being planned to further characterize its potential therapeutic role.
The asthma symptoms of the patient in this case responded to benralizumab in a manner consistent with the aggregate responses in patients in the Q8W arm of the CALIMA trial, with a reduced 56-week exacerbation rate, improved lung function, reduced asthma symptom score, and near-total depletion of blood eosinophils. The observed reduction in AD symptoms occurred concurrent with that response, as is evident in Fig. 1, with a substantial decrease in inflammation at 2 months compared with baseline, and skin healing at 5 months. It is noteworthy that the improvements in the patient’s AD symptoms occurred in the absence of any systemic steroid use for asthma exacerbation; the patient received systemic steroids only once during the study period, on day 363.
It is important to acknowledge that the findings reported here were incidental, observed during a case that was part of a large prospective clinical trial. A post hoc attempt to identify other patients in the study with similar findings would be practically infeasible and limited by unavoidable selection bias. However, the strength of the observed effect in this case suggests a potential area for investigation.
In conclusion, we observed spontaneous resolution of AD coincident with participation in a clinical trial for benralizumab to treat severe, uncontrolled, eosinophilic asthma. Given the plausible overlap in pathologic mechanisms between asthma and AD, further studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be efficacious in managing multiple allergic diseases.
Abbreviations
ACQ-6 Asthma Control Questionnaire-6
AD Atopic dermatitis
FEV1 Forced expiratory volume in 1 second
ICS Inhaled corticosteroids
IgE Immunoglobulin E
IL-5/IL-5R Interleukin-5/interleukin-5 receptor
LABA Long-acting β2-agonist
mAb Monoclonal antibody
Q4W CALIMA study group: benralizumab 30 mg every 4 weeks
Q8W CALIMA study group: benralizumab 30 mg every 8 weeks, first three doses 4 weeks apart
Acknowledgements
Jeanne McAdara PhD and Citrus Healthcare Communications Group provided professional medical writing assistance, which was funded by AstraZeneca.
Author’s information
Dr. Pham’s career in medical research and practice has focused on studying mechanisms in T cell development and T cell-mediated immune and allergy responses. He attended medical school at the University of Maryland, completed an immunology research fellowship at the National Institute of Allergy and Infectious Diseases, a residency in internal medicine at Tulane University, and another fellowship in pulmonary critical care research and medicine at the University of Colorado and National Jewish Health.
Authors' contributions
As the sole author, DNP collected patient data, oversaw drafting of the manuscript, provided critical review, and approved the manuscript for submission. The author read and approved the final manuscript.
Funding
AstraZeneca provided funding for professional medical writing assistance.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The patient’s legal guardian gave informed consent for the patient to participate in the CALIMA clinical trial.
Consent for publication
Written informed consent was obtained from the patient and her legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
DNP declares that he has no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AS NEEDED | DrugDosageText | CC BY | 33673870 | 19,120,052 | 2021-03-06 |
What was the dosage of drug 'BUDESONIDE\FORMOTEROL'? | Spontaneous resolution of atopic dermatitis incidental to participation in benralizumab clinical trial for severe, uncontrolled asthma: a case report.
BACKGROUND
T cell-mediated eosinophilia is associated with numerous conditions-including atopic dermatitis, food allergies, and asthma-collectively known as the "atopic march." Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody directed against the ⍺ chain of the eosinophil cell surface receptor IL-5R. Benralizumab treatment causes near-complete depletion of circulating eosinophils and was approved in 2017 for add-on, maintenance treatment of severe asthma with an eosinophilic phenotype, based on the results of the CALIMA and SIROCCO pivotal trials. Benralizumab is not currently approved for the treatment of eosinophilic conditions besides asthma; however, during the CALIMA trial, spontaneous resolution of atopic dermatitis was observed in a patient, concurrent with reduction in her asthma symptoms.
METHODS
In January 2015, a 14-year-old Asian girl with severe, uncontrolled asthma was enrolled in CALIMA. The patient's baseline eosinophil blood count was 1200 cells/μL, her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9 and her asthma exacerbation rate in the prior year was 4. She also displayed a pronounced, pruritic, chronic, inflammatory rash consistent with atopic dermatitis across her face. The investigator was blinded to the patient's treatment group during treatment; however, her asthma symptoms diminished over the course of the study (FEV1 at 56 weeks, 3.01 L/110.5% (pre) and 3.25 L/119.3% (post); overall asthma symptom score 2.1; one influenza-associated exacerbation). Furthermore, her atopic dermatitis symptoms resolved spontaneously within the first 5 months of the study. After unblinding, the patient was confirmed to have been randomized to an active treatment arm, and her blood eosinophil count had dropped below the limit of detection after the first study dose.
CONCLUSIONS
Given the potential shared mechanisms between eosinophilic asthma and atopic dermatitis, it is plausible that benralizumab-induced eosinopenia factored into the resolution of the patient's atopic dermatitis. Further clinical studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be useful in managing multiple conditions associated with eosinophilia.
Background
Eczema, or atopic dermatitis (AD), is a chronic, pruritic, inflammatory skin condition with a mechanism linked to deficiency of function in the skin barrier [1, 2]. Challenge by environmental allergens and pathogenic microbes precipitates a complex and exaggerated pro-inflammatory T cell response that includes interleukin-5 (IL-5) stimulation of eosinophil proliferation, activation, and subsequent overproduction of immunoglobulin E (IgE) [1, 2]. AD tends to precede or co-occur with other allergic diseases such as food allergies, severe eosinophilic asthma, and allergic rhinitis. It is increasingly understood that the physiologic mechanisms underlying these disorders overlap and may be part of a pathologic cascade [3].
The potential links between these allergic diseases point to a number of attractive therapeutic targets, including IgE antibodies, IL-5, and eosinophils, which are stimulated through the cell surface receptor, IL-5R [4–6]. Several pharmaceutical agents have been approved or are currently in development that are designed to disrupt the IL-5/IL-5R interaction in eosinophilic asthma, AD, or other allergic diseases [4]. However, it is not yet known whether agents developed against one indication will show efficacy against others within the constellation of atopic diseases.
Here, we report spontaneous resolution of AD in an adolescent patient participating in the phase 3 CALIMA pivotal trial, which evaluated the safety and efficacy of the anti-IL-5R mAb benralizumab as an add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts [7].
Case presentation
In December 2013, a 14-year-old Asian girl (body mass index 22.34; never-smoker) was referred to our practice with severe, uncontrolled asthma, which was first diagnosed in 2009. At the time of referral, the patient was taking budesonide 160 μg and formoterol 4.5 μg, two puffs twice daily plus formoterol 18 μg daily. Her history was also significant for allergic rhinitis, AD, and IgE-confirmed allergies to an extensive panel of foods and to animal dander.
Her medications were adjusted to budesonide 160 μg and formoterol 4.5 μg taken as two puffs twice-daily, montelukast 5 mg daily, and salbutamol as needed; however, this regimen did not achieve satisfactory symptom control. In December 2014 she was screened for potential enrollment into the CALIMA clinical trial [7].
At the enrollment visit in January 2015, the patient’s eosinophil blood count was 1200 cells/μL. Her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9. She had experienced four asthma exacerbations requiring treatment with systemic corticosteroids in the year prior to enrollment. Furthermore, a pronounced, pruritic, inflammatory rash consistent with AD was evident on the patient’s cheeks and forehead (Fig. 1, left panel). The patient and her guardian confirmed that the rash was chronic, and it was documented photographically as part of the patient record. Following completion of pre-enrollment screening and informed consent from her guardian, the patient was enrolled in the study and underwent the specified 4-week screening and run-in period [7]. She met all selection criteria and was randomized to blinded treatment assignment in January 2015. The patient completed a study visit every 4 weeks for 56 weeks for data collection and subcutaneous injection of her assigned study drug, and attended the 60-week final study visit. The patient was 100% compliant with the schedule and all study procedures. During the study, the patient continued using her background asthma controller medications, and was allowed to use albuterol two puffs, four times per day as needed as her rescue medication.Fig. 1 Progressive resolution of eczematous lesions in a patient participating in the CALIMA randomized clinical trial evaluating benralizumab as an add-on treatment for severe asthma with eosinophilic phenotype. The pictures were taken on the basis of clinical observation and without knowledge of the patient’s assigned dose group. After the trial was completed and unblinded, the patient was found to be in the treatment arm that received benralizumab 30 mg every 8 weeks, with the first three doses every 4 weeks, and in the primary analysis population of patients with at least 300 eosinophils/μL peripheral blood
As CALIMA was a randomized, double-blind, placebo-controlled, parallel-group trial [7], it was not known to which arm the patient had been randomized and her eosinophil counts were redacted during the study and were unknown to the investigator or patient. However, during the course of treatment, the patient noted fewer asthma symptoms and reduced dyspnea during activities. Furthermore, a consistent and progressive resolution of her AD symptoms was observed and documented over 5 months (Fig. 1, middle and right panels). She experienced a single exacerbation requiring systemic corticosteroid treatment on day 363 of the study (December 2015), coincident with an influenza infection.
After the study was completed and unblinded, the patient was confirmed to have received 30 mg benralizumab every 8 weeks over the course of the 56-week treatment period, with the first three doses administered 4 weeks apart (the “Q8W” study arm). Her data were confirmed to have been included in the primary (intention-to-treat) analysis of patients with eosinophil count of at least 300 cells/μL.
At her 56-week study visit, the patient’s pre-bronchodilator FEV1 was 3.01 L (FEV1/FVC 110.5%), whereas her post-bronchodilator FEV1 was 3.3 L (FEV1/FVC 119.3%). Therefore, during the course of the study she gained 1.1 L in pre-bronchodilator FEV1. Furthermore, the patient’s overall asthma symptom score at 56 weeks was 2.1, a decrease of 1.8 points compared to baseline. For reference, in the CALIMA placebo group (n = 248), the least-squares mean change in pre-bronchodilator FEV1 was a 0.22-L increase, and the least-squares mean change in asthma symptom score was − 1.2 [7].
Furthermore, the patient’s blood eosinophil count dropped below the limit of detection by the 4-week visit (after one study dose) and remained there throughout the 56-week duration of the study.
Discussion and conclusions
This case is notable in that the patient was enrolled in a clinical trial focused on a specific drug indication—severe, uncontrolled asthma with elevated blood eosinophil counts—but experienced dramatic resolution of symptoms for a different condition that may have a related mechanism of action. Evidence is increasing that the pathology of asthma, AD, and other diseases that are part of the so-called atopic march are a result of a self-reinforcing and progressive cascade of epithelial barrier dysfunction in the skin, gut mucosa, and respiratory mucosa, allowing increased penetration of allergens and microbes that elicit a systemic, T cell-mediated eosinophilic hyper-response [2, 3, 8]. Because this inappropriate eosinophilic response is characteristic of all of the atopic diseases, it is conceivable that treatments targeting the underlying T cell–eosinophil interaction could potentially show efficacy against more than one condition [2–6]. However this hypothesis must be investigated for each combination of drug and condition and the therapies currently on the market are, so far, limited to single indications.
Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody (mAb) directed against the ⍺ chain of IL-5R, a receptor that is abundant on the surface of eosinophils and basophils and is essential to their function and survival [9, 10]. The engineered afucosylation enhances the receptor binding affinity of benralizumab as well as its antibody-dependent cell-mediated cytotoxicity function [9], resulting in near-total depletion of eosinophils from the circulation, and from the airways and lungs, and approximately 80% depletion of eosinophilic progenitors from the bone marrow [10, 11].
CALIMA was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 clinical trial conducted at 303 sites in 11 countries [7]. Patients enrolled in the study were aged 12–75 years with severe asthma uncontrolled by medium- to high-dose inhaled corticosteroids (ICS) with long-acting β2-agonists (LABA) and a history of two or more exacerbations in the previous year. Patients were randomized in a 1:1:1 ratio to receive 56 weeks of treatment with benralizumab 30 mg subcutaneous every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo. The study population was also stratified (2:1) by baseline blood eosinophil counts (at least 300 cells/μL versus less than 300 cells/μL). The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dose ICS plus LABA with baseline blood eosinophils at least 300 cells/μL (intent-to-treat analysis). Secondary endpoints were FEV1 and total asthma symptom score.
Of 2505 patients enrolled and 1306 randomized, 728 patients were included in the primary analysis population. The study found that 56 weeks of add-on therapy with benralizumab at either dose level reduced annual exacerbation rates in patients with severe asthma and elevated baseline blood eosinophil counts by up to 36% compared with placebo (Q4W rate ratio 0.64 [95% CI 0.49–0.85], p = 0.0018, n = 241; and Q8W rate ratio 0.72 [95% CI 0.54–0.95], p = 0.0188, n = 239). Benralizumab also significantly improved pre-bronchodilator FEV1 in the Q4W and Q8W groups, and total asthma symptom score in the Q8W group. Furthermore, patients in both active dose groups experienced near-complete depletion of blood eosinophils by the 4-week sampling time point. The drug was well tolerated with few drug-related adverse events.
On the basis of the results of CALIMA and another pivotal trial, SIROCCO [7, 12], benralizumab was approved in 2017 by the US Food and Drug Administration as Fasenra® for add-on maintenance treatment of patients with severe asthma, aged 12 years and older, with an eosinophilic phenotype [13]. The medication is not approved for treatment of other eosinophilic conditions and is not for relief of acute bronchospasm or status asthmaticus. Results from the first year of a long-term safety study (the BORA phase 3 extension trial) are consistent with efficacy and safety outcomes from the pivotal trials [14]. To date, benralizumab has not been evaluated clinically for its efficacy against AD, although a phase 2 study is being planned to further characterize its potential therapeutic role.
The asthma symptoms of the patient in this case responded to benralizumab in a manner consistent with the aggregate responses in patients in the Q8W arm of the CALIMA trial, with a reduced 56-week exacerbation rate, improved lung function, reduced asthma symptom score, and near-total depletion of blood eosinophils. The observed reduction in AD symptoms occurred concurrent with that response, as is evident in Fig. 1, with a substantial decrease in inflammation at 2 months compared with baseline, and skin healing at 5 months. It is noteworthy that the improvements in the patient’s AD symptoms occurred in the absence of any systemic steroid use for asthma exacerbation; the patient received systemic steroids only once during the study period, on day 363.
It is important to acknowledge that the findings reported here were incidental, observed during a case that was part of a large prospective clinical trial. A post hoc attempt to identify other patients in the study with similar findings would be practically infeasible and limited by unavoidable selection bias. However, the strength of the observed effect in this case suggests a potential area for investigation.
In conclusion, we observed spontaneous resolution of AD coincident with participation in a clinical trial for benralizumab to treat severe, uncontrolled, eosinophilic asthma. Given the plausible overlap in pathologic mechanisms between asthma and AD, further studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be efficacious in managing multiple allergic diseases.
Abbreviations
ACQ-6 Asthma Control Questionnaire-6
AD Atopic dermatitis
FEV1 Forced expiratory volume in 1 second
ICS Inhaled corticosteroids
IgE Immunoglobulin E
IL-5/IL-5R Interleukin-5/interleukin-5 receptor
LABA Long-acting β2-agonist
mAb Monoclonal antibody
Q4W CALIMA study group: benralizumab 30 mg every 4 weeks
Q8W CALIMA study group: benralizumab 30 mg every 8 weeks, first three doses 4 weeks apart
Acknowledgements
Jeanne McAdara PhD and Citrus Healthcare Communications Group provided professional medical writing assistance, which was funded by AstraZeneca.
Author’s information
Dr. Pham’s career in medical research and practice has focused on studying mechanisms in T cell development and T cell-mediated immune and allergy responses. He attended medical school at the University of Maryland, completed an immunology research fellowship at the National Institute of Allergy and Infectious Diseases, a residency in internal medicine at Tulane University, and another fellowship in pulmonary critical care research and medicine at the University of Colorado and National Jewish Health.
Authors' contributions
As the sole author, DNP collected patient data, oversaw drafting of the manuscript, provided critical review, and approved the manuscript for submission. The author read and approved the final manuscript.
Funding
AstraZeneca provided funding for professional medical writing assistance.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The patient’s legal guardian gave informed consent for the patient to participate in the CALIMA clinical trial.
Consent for publication
Written informed consent was obtained from the patient and her legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
DNP declares that he has no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 160 (+) 4.5 MICROGRAM | DrugDosageText | CC BY | 33673870 | 19,120,052 | 2021-03-06 |
What was the dosage of drug 'MONTELUKAST SODIUM'? | Spontaneous resolution of atopic dermatitis incidental to participation in benralizumab clinical trial for severe, uncontrolled asthma: a case report.
BACKGROUND
T cell-mediated eosinophilia is associated with numerous conditions-including atopic dermatitis, food allergies, and asthma-collectively known as the "atopic march." Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody directed against the ⍺ chain of the eosinophil cell surface receptor IL-5R. Benralizumab treatment causes near-complete depletion of circulating eosinophils and was approved in 2017 for add-on, maintenance treatment of severe asthma with an eosinophilic phenotype, based on the results of the CALIMA and SIROCCO pivotal trials. Benralizumab is not currently approved for the treatment of eosinophilic conditions besides asthma; however, during the CALIMA trial, spontaneous resolution of atopic dermatitis was observed in a patient, concurrent with reduction in her asthma symptoms.
METHODS
In January 2015, a 14-year-old Asian girl with severe, uncontrolled asthma was enrolled in CALIMA. The patient's baseline eosinophil blood count was 1200 cells/μL, her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9 and her asthma exacerbation rate in the prior year was 4. She also displayed a pronounced, pruritic, chronic, inflammatory rash consistent with atopic dermatitis across her face. The investigator was blinded to the patient's treatment group during treatment; however, her asthma symptoms diminished over the course of the study (FEV1 at 56 weeks, 3.01 L/110.5% (pre) and 3.25 L/119.3% (post); overall asthma symptom score 2.1; one influenza-associated exacerbation). Furthermore, her atopic dermatitis symptoms resolved spontaneously within the first 5 months of the study. After unblinding, the patient was confirmed to have been randomized to an active treatment arm, and her blood eosinophil count had dropped below the limit of detection after the first study dose.
CONCLUSIONS
Given the potential shared mechanisms between eosinophilic asthma and atopic dermatitis, it is plausible that benralizumab-induced eosinopenia factored into the resolution of the patient's atopic dermatitis. Further clinical studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be useful in managing multiple conditions associated with eosinophilia.
Background
Eczema, or atopic dermatitis (AD), is a chronic, pruritic, inflammatory skin condition with a mechanism linked to deficiency of function in the skin barrier [1, 2]. Challenge by environmental allergens and pathogenic microbes precipitates a complex and exaggerated pro-inflammatory T cell response that includes interleukin-5 (IL-5) stimulation of eosinophil proliferation, activation, and subsequent overproduction of immunoglobulin E (IgE) [1, 2]. AD tends to precede or co-occur with other allergic diseases such as food allergies, severe eosinophilic asthma, and allergic rhinitis. It is increasingly understood that the physiologic mechanisms underlying these disorders overlap and may be part of a pathologic cascade [3].
The potential links between these allergic diseases point to a number of attractive therapeutic targets, including IgE antibodies, IL-5, and eosinophils, which are stimulated through the cell surface receptor, IL-5R [4–6]. Several pharmaceutical agents have been approved or are currently in development that are designed to disrupt the IL-5/IL-5R interaction in eosinophilic asthma, AD, or other allergic diseases [4]. However, it is not yet known whether agents developed against one indication will show efficacy against others within the constellation of atopic diseases.
Here, we report spontaneous resolution of AD in an adolescent patient participating in the phase 3 CALIMA pivotal trial, which evaluated the safety and efficacy of the anti-IL-5R mAb benralizumab as an add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts [7].
Case presentation
In December 2013, a 14-year-old Asian girl (body mass index 22.34; never-smoker) was referred to our practice with severe, uncontrolled asthma, which was first diagnosed in 2009. At the time of referral, the patient was taking budesonide 160 μg and formoterol 4.5 μg, two puffs twice daily plus formoterol 18 μg daily. Her history was also significant for allergic rhinitis, AD, and IgE-confirmed allergies to an extensive panel of foods and to animal dander.
Her medications were adjusted to budesonide 160 μg and formoterol 4.5 μg taken as two puffs twice-daily, montelukast 5 mg daily, and salbutamol as needed; however, this regimen did not achieve satisfactory symptom control. In December 2014 she was screened for potential enrollment into the CALIMA clinical trial [7].
At the enrollment visit in January 2015, the patient’s eosinophil blood count was 1200 cells/μL. Her pre-bronchodilator forced expiratory volume in 1 second (FEV1) was 1.9 L and FEV1/forced vital capacity (FVC) ratio was 71.4%, and her post-bronchodilator FEV1 was 3.2 L (FEV1/FVC of 115.9%). Her overall baseline asthma symptom score was 3.9. She had experienced four asthma exacerbations requiring treatment with systemic corticosteroids in the year prior to enrollment. Furthermore, a pronounced, pruritic, inflammatory rash consistent with AD was evident on the patient’s cheeks and forehead (Fig. 1, left panel). The patient and her guardian confirmed that the rash was chronic, and it was documented photographically as part of the patient record. Following completion of pre-enrollment screening and informed consent from her guardian, the patient was enrolled in the study and underwent the specified 4-week screening and run-in period [7]. She met all selection criteria and was randomized to blinded treatment assignment in January 2015. The patient completed a study visit every 4 weeks for 56 weeks for data collection and subcutaneous injection of her assigned study drug, and attended the 60-week final study visit. The patient was 100% compliant with the schedule and all study procedures. During the study, the patient continued using her background asthma controller medications, and was allowed to use albuterol two puffs, four times per day as needed as her rescue medication.Fig. 1 Progressive resolution of eczematous lesions in a patient participating in the CALIMA randomized clinical trial evaluating benralizumab as an add-on treatment for severe asthma with eosinophilic phenotype. The pictures were taken on the basis of clinical observation and without knowledge of the patient’s assigned dose group. After the trial was completed and unblinded, the patient was found to be in the treatment arm that received benralizumab 30 mg every 8 weeks, with the first three doses every 4 weeks, and in the primary analysis population of patients with at least 300 eosinophils/μL peripheral blood
As CALIMA was a randomized, double-blind, placebo-controlled, parallel-group trial [7], it was not known to which arm the patient had been randomized and her eosinophil counts were redacted during the study and were unknown to the investigator or patient. However, during the course of treatment, the patient noted fewer asthma symptoms and reduced dyspnea during activities. Furthermore, a consistent and progressive resolution of her AD symptoms was observed and documented over 5 months (Fig. 1, middle and right panels). She experienced a single exacerbation requiring systemic corticosteroid treatment on day 363 of the study (December 2015), coincident with an influenza infection.
After the study was completed and unblinded, the patient was confirmed to have received 30 mg benralizumab every 8 weeks over the course of the 56-week treatment period, with the first three doses administered 4 weeks apart (the “Q8W” study arm). Her data were confirmed to have been included in the primary (intention-to-treat) analysis of patients with eosinophil count of at least 300 cells/μL.
At her 56-week study visit, the patient’s pre-bronchodilator FEV1 was 3.01 L (FEV1/FVC 110.5%), whereas her post-bronchodilator FEV1 was 3.3 L (FEV1/FVC 119.3%). Therefore, during the course of the study she gained 1.1 L in pre-bronchodilator FEV1. Furthermore, the patient’s overall asthma symptom score at 56 weeks was 2.1, a decrease of 1.8 points compared to baseline. For reference, in the CALIMA placebo group (n = 248), the least-squares mean change in pre-bronchodilator FEV1 was a 0.22-L increase, and the least-squares mean change in asthma symptom score was − 1.2 [7].
Furthermore, the patient’s blood eosinophil count dropped below the limit of detection by the 4-week visit (after one study dose) and remained there throughout the 56-week duration of the study.
Discussion and conclusions
This case is notable in that the patient was enrolled in a clinical trial focused on a specific drug indication—severe, uncontrolled asthma with elevated blood eosinophil counts—but experienced dramatic resolution of symptoms for a different condition that may have a related mechanism of action. Evidence is increasing that the pathology of asthma, AD, and other diseases that are part of the so-called atopic march are a result of a self-reinforcing and progressive cascade of epithelial barrier dysfunction in the skin, gut mucosa, and respiratory mucosa, allowing increased penetration of allergens and microbes that elicit a systemic, T cell-mediated eosinophilic hyper-response [2, 3, 8]. Because this inappropriate eosinophilic response is characteristic of all of the atopic diseases, it is conceivable that treatments targeting the underlying T cell–eosinophil interaction could potentially show efficacy against more than one condition [2–6]. However this hypothesis must be investigated for each combination of drug and condition and the therapies currently on the market are, so far, limited to single indications.
Benralizumab is a recombinant, humanized, afucosylated monoclonal antibody (mAb) directed against the ⍺ chain of IL-5R, a receptor that is abundant on the surface of eosinophils and basophils and is essential to their function and survival [9, 10]. The engineered afucosylation enhances the receptor binding affinity of benralizumab as well as its antibody-dependent cell-mediated cytotoxicity function [9], resulting in near-total depletion of eosinophils from the circulation, and from the airways and lungs, and approximately 80% depletion of eosinophilic progenitors from the bone marrow [10, 11].
CALIMA was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 clinical trial conducted at 303 sites in 11 countries [7]. Patients enrolled in the study were aged 12–75 years with severe asthma uncontrolled by medium- to high-dose inhaled corticosteroids (ICS) with long-acting β2-agonists (LABA) and a history of two or more exacerbations in the previous year. Patients were randomized in a 1:1:1 ratio to receive 56 weeks of treatment with benralizumab 30 mg subcutaneous every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo. The study population was also stratified (2:1) by baseline blood eosinophil counts (at least 300 cells/μL versus less than 300 cells/μL). The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dose ICS plus LABA with baseline blood eosinophils at least 300 cells/μL (intent-to-treat analysis). Secondary endpoints were FEV1 and total asthma symptom score.
Of 2505 patients enrolled and 1306 randomized, 728 patients were included in the primary analysis population. The study found that 56 weeks of add-on therapy with benralizumab at either dose level reduced annual exacerbation rates in patients with severe asthma and elevated baseline blood eosinophil counts by up to 36% compared with placebo (Q4W rate ratio 0.64 [95% CI 0.49–0.85], p = 0.0018, n = 241; and Q8W rate ratio 0.72 [95% CI 0.54–0.95], p = 0.0188, n = 239). Benralizumab also significantly improved pre-bronchodilator FEV1 in the Q4W and Q8W groups, and total asthma symptom score in the Q8W group. Furthermore, patients in both active dose groups experienced near-complete depletion of blood eosinophils by the 4-week sampling time point. The drug was well tolerated with few drug-related adverse events.
On the basis of the results of CALIMA and another pivotal trial, SIROCCO [7, 12], benralizumab was approved in 2017 by the US Food and Drug Administration as Fasenra® for add-on maintenance treatment of patients with severe asthma, aged 12 years and older, with an eosinophilic phenotype [13]. The medication is not approved for treatment of other eosinophilic conditions and is not for relief of acute bronchospasm or status asthmaticus. Results from the first year of a long-term safety study (the BORA phase 3 extension trial) are consistent with efficacy and safety outcomes from the pivotal trials [14]. To date, benralizumab has not been evaluated clinically for its efficacy against AD, although a phase 2 study is being planned to further characterize its potential therapeutic role.
The asthma symptoms of the patient in this case responded to benralizumab in a manner consistent with the aggregate responses in patients in the Q8W arm of the CALIMA trial, with a reduced 56-week exacerbation rate, improved lung function, reduced asthma symptom score, and near-total depletion of blood eosinophils. The observed reduction in AD symptoms occurred concurrent with that response, as is evident in Fig. 1, with a substantial decrease in inflammation at 2 months compared with baseline, and skin healing at 5 months. It is noteworthy that the improvements in the patient’s AD symptoms occurred in the absence of any systemic steroid use for asthma exacerbation; the patient received systemic steroids only once during the study period, on day 363.
It is important to acknowledge that the findings reported here were incidental, observed during a case that was part of a large prospective clinical trial. A post hoc attempt to identify other patients in the study with similar findings would be practically infeasible and limited by unavoidable selection bias. However, the strength of the observed effect in this case suggests a potential area for investigation.
In conclusion, we observed spontaneous resolution of AD coincident with participation in a clinical trial for benralizumab to treat severe, uncontrolled, eosinophilic asthma. Given the plausible overlap in pathologic mechanisms between asthma and AD, further studies are warranted to determine whether benralizumab or other drugs targeted against IL-5/IL-5R may be efficacious in managing multiple allergic diseases.
Abbreviations
ACQ-6 Asthma Control Questionnaire-6
AD Atopic dermatitis
FEV1 Forced expiratory volume in 1 second
ICS Inhaled corticosteroids
IgE Immunoglobulin E
IL-5/IL-5R Interleukin-5/interleukin-5 receptor
LABA Long-acting β2-agonist
mAb Monoclonal antibody
Q4W CALIMA study group: benralizumab 30 mg every 4 weeks
Q8W CALIMA study group: benralizumab 30 mg every 8 weeks, first three doses 4 weeks apart
Acknowledgements
Jeanne McAdara PhD and Citrus Healthcare Communications Group provided professional medical writing assistance, which was funded by AstraZeneca.
Author’s information
Dr. Pham’s career in medical research and practice has focused on studying mechanisms in T cell development and T cell-mediated immune and allergy responses. He attended medical school at the University of Maryland, completed an immunology research fellowship at the National Institute of Allergy and Infectious Diseases, a residency in internal medicine at Tulane University, and another fellowship in pulmonary critical care research and medicine at the University of Colorado and National Jewish Health.
Authors' contributions
As the sole author, DNP collected patient data, oversaw drafting of the manuscript, provided critical review, and approved the manuscript for submission. The author read and approved the final manuscript.
Funding
AstraZeneca provided funding for professional medical writing assistance.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The patient’s legal guardian gave informed consent for the patient to participate in the CALIMA clinical trial.
Consent for publication
Written informed consent was obtained from the patient and her legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
DNP declares that he has no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 5 MILLIGRAM, DAILY (QD) | DrugDosageText | CC BY | 33673870 | 19,120,052 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Antineutrophil cytoplasmic antibody increased'. | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZATHIOPRINE, INFLIXIMAB, RITUXIMAB, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY | 33676553 | 19,084,316 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exophthalmos'. | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZATHIOPRINE, CYCLOPHOSPHAMIDE, METHOTREXATE, METHYLPREDNISOLONE, PREDNISOLONE, RITUXIMAB | DrugsGivenReaction | CC BY | 33676553 | 19,475,619 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Headache'. | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZATHIOPRINE, CYCLOPHOSPHAMIDE, METHOTREXATE, METHYLPREDNISOLONE, PREDNISOLONE, RITUXIMAB | DrugsGivenReaction | CC BY | 33676553 | 19,475,619 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lacrimation increased'. | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZATHIOPRINE, CYCLOPHOSPHAMIDE, METHOTREXATE, METHYLPREDNISOLONE, PREDNISOLONE, RITUXIMAB | DrugsGivenReaction | CC BY | 33676553 | 19,475,619 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZATHIOPRINE, INFLIXIMAB, RITUXIMAB, SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY | 33676553 | 19,084,316 | 2021-03-06 |
What was the administration route of drug 'INFLIXIMAB'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33676553 | 19,046,927 | 2021-03-06 |
What was the administration route of drug 'RITUXIMAB'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33676553 | 19,475,619 | 2021-03-06 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 15 MG/KG MONTHLY | DrugDosageText | CC BY | 33676553 | 19,475,619 | 2021-03-06 |
What was the dosage of drug 'METHOTREXATE'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 15 MG, 1/WEEK | DrugDosageText | CC BY | 33676553 | 19,475,619 | 2021-03-06 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 1 G/DAY PULSED METHYLPREDNISOLONE FOR 3 DAYS, THEN 1 MG/KG/DAY FOR FURTHER 10 DAYS | DrugDosageText | CC BY | 33676553 | 19,475,619 | 2021-03-06 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | UNK?10 YEARS | DrugDosageText | CC BY | 33676553 | 19,084,316 | 2021-03-06 |
What was the outcome of reaction 'Disease progression'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33676553 | 19,046,927 | 2021-03-06 |
What was the outcome of reaction 'Granulomatosis with polyangiitis'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33676553 | 19,046,927 | 2021-03-06 |
What was the outcome of reaction 'Orbital granuloma'? | Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis.
BACKGROUND
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA.
METHODS
We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred.
CONCLUSIONS
This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
Background
Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease with unidentified etiology characterized by small/medium vessel vasculitis, granulomatous inflammation and tissue necrosis. Its clinical presentation is highly variable and severe cases with organ involvement are not uncommon. Among them, eye complications occur in 50–60 % of patients and usually present as necrotizing scleritis or granulomatous orbital involvement. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and long-lasting facial deformity [1, 2].
Case presentation
We report a 45-year-old Caucasian male diagnosed with GPA in 2001 presenting with rhinitis, sinubronchitis and a right exophthalmos, but not signs of diplopia or vision defects. The nasal mucosa showed in two different biopsies active inflammation characterized by the presence of neutrophils and active vasculitis, tissue necrosis, and granulomatous inflammation. In the lacrimal ducts, a partially scarred tissue with moderate to severe chronic signs of inflammation was observed. Lab testing revealed anti-neutrophil cytoplasmic antibodies (cANCA) and against proproteinase-3 (anti-PR3). The patient was a non-smoker and had an unapparent medical history. No signs of kidney, lung, and joint, skin or central nervous system involvement were found.
The patient met the 1990 American College of Rheumatology (ACR) classification criteria for GPA [3]. Based on the clinical practice in 2001, when rituximab was not yet available for the treatment of GPA, intermittent cycles of cyclophosphamide at 15 mg/kg every month were started and the patient later received stable doses of methotrexate (15 mg/week) and low doses of glucocorticoids (5 mg daily) as maintenance treatment. In 2010 symptoms worsened, with increasing complaints related to inflammation of the upper airways (rhinitis, sinusitis and bronchitis) requiring hospital admission and the start of high-dose steroids (1 g/day pulsed methylprednisolone for 3 days, then 1 mg/kg/day for further 10 days. Cyclophosphamide (cumulative doses of 7 g) was stopped Rituximab was initiated at doses of 1000 mg at weeks 0–2 and then 500 mg every 6 months thereafter.
GPAthen remained silent with rituximab, methotrexate (15 mg/week) and low-dose prednisolone (5 mg daily) over 1-year. Because of family planning, methotrexate was replaced by azathioprine (150 mg/day), prednisolone was stopped and rituximab was continued. Three months later, the patient presented with persistent frontal headache, protrusion of the right eyeball and increased eye watering. Conventional MRI showed a granulomatous mass in the area of the right orbita, with granulomatous changes in the left lacrimal gland, indicating progression of disease despite rituximab treatment and almost complete B-lymphocyte depletion.
In agreement with the patient and considering the substantial granuloma formation in the orbita infliximab was added to rituximab at 400 mg IV at weeks 0–2–6 and every 6 weeks thereafter. A remarkable improvement in symptoms and inflammation imaging after a 6-month follow-up was observed. This combination regimen of azathioprine, rituximab and infliximab was maintained and the patient achieved long-standing remission without infectious complications. A trimethoprim/sulfamethoxazole prophylaxis has been maintained for the last 10 years, which potentially mitigated infections. No adverse events occurred during the entire 10 years of treatment. Despite remission, ANCA remained consistently elevated during this time (Fig. 1), even considering the methods change for ANCA tests, from ELISA to chemiluninescence technique, which has been standardized and validated in our center according to international guidelines.. Currently, the patient has no complaints, the treatment has been well tolerated and MRI revealed only minimal residual lesions (3 mm in size) in the orbita in the 2019 follow-up. Fig. 1 cANCA/PR3 levels in the last 15 years of treatment. The dotted line indicates the upper limit of the reached cANCA/PR3, the blue line indicates the upper limit of the normal range for cANCA/PR3. RTX rituximab, IFX infliximab, AZA azathioprin
Conclusions
Rituximab has strongly improved the treatment of GPA including eye manifestations [4–6]. However, in our particular case rituximab treatment had not suffice. Our patient initially responded to rituximab but then showed recurrence of disease despite almost complete B lymphocyte depletion. Based on the granulomatous lesion in the orbita leading to exophthalmus we decided to add infliximab to rituximab and achieved long-term response. In two previous publications it was reported, that a patient diagnosed with GPA received a sequential treatment with cyclophosphamide, then with infliximab and, due to recurrence of symptoms with rituximab [7]. In another patient with a delayed diagnosis of GPA due to an unusual presentation, sequential treatment with steroids and infliximab was started, and then due to relapse the patient was treated with three courses of cyclophosphamide and a posteriori with rituximab [8].
This case report suggests that the use of a combination of rituximab and infliximab might be a promising strategy for the treatment of refractory GPA, the combination treatment has been well tolerated for a long time under tight monitoring and did not trigger an immune state that precipitates adverse events. We are aware of the fact that the use of two biological agents might imply an increased risk life-threatening infections or malignancies. It has been reported in 2012 that increased risk of both solid and hematologic malignancies in ANCA associated vasculitis, this publication states that the risk might be both, inherent to the disease or to the treatment, which is difficult to determine [9].
Acknowledgements
Not applicable.
Authors' contributions
LVM, AK, JR, BM and GS contributed to the treatment design and patient management; LVM conceived the presented idea and wrote the paper with input from BM and GS. All authors gave consent for publication. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. No financial support was received from any funding bodies in the public or commercial to carry out the work described in this manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written informed consent for clinical details publication was obtained from the patient. A copy of the consent form is available for review by the Editor of the journal.
Competing interests
The authors declare that they have no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33676553 | 19,046,927 | 2021-03-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Dichotomic response to interleukin-6 blockade in idiopathic multicentric Castleman disease: two case reports.
BACKGROUND
Human herpervirus-8/human immunodeficiency virus negative Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder sustained by a pro-inflammatory condition of hypercytokinemia mostly mediated by Interleukin-6 (IL-6). According to iMCD consensus guidelines, anti-IL-6 blockade should be the first-line therapy for iMCD. However, despite the existing therapeutic alternatives, a large proportion of iMCD patients still lacks an effective therapy.
METHODS
Here, we report two real-life iMCD cases with a different response to IL-6 blockade. The first presented patient obtained a prompt resolution of symptoms and a complete regression of adenopathies after IL-6 blockade therapy administration. Conversely, the second patient did not respond neither to Rituximab and Etoposide association nor to IL-6 blockade therapy (both Siltuximab and Tocilizumab). Furthermore, Intravenous immunoglobulin, Cyclosporine A, Sirolimus and anti-Interleukin-1 Anakinra were all attempted without any results. Since no treatment was successful, after a further confirmation of iMCD diagnosis by a second lymph node biopsy, patient has been candidate for thalidomide, cyclophosphamide and prednisone association therapy.
CONCLUSIONS
The iMCD cases we reported are coherent with the evidences that IL-6 blockade is a safe and an effective therapy for iMCD. Despite this, more than half of patients do not respond to anti IL-6 drugs. In such cases, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone. However, the two reported iMCD cases, confirm the need to more deeply investigate iMCD pathogenesis and to better dissect the heterogeneity of the disease in order to develop novel, effective therapeutic strategies.
Background
Castleman disease (CD) consists of an uncommon series of lymphoproliferative disorders comprehending several subsets. Among them, human herpervirus-8/human immunodeficiency virus (HHV-8/HIV) negative Idiopathic multicentric Castleman disease (iMCD) still remains one of the less properly understood subset(1). iMCD onset may include manifestations such as multiple lymphadenopathies, hepatosplenomegaly, cytopenias, and organ dysfunction. Furthermore, iMCD is classified into two categories (nonsevere or severe) according to Castleman disease collaborative network (CDCN) severity criteria based on patient performance status and organ dysfunction including renal disfunction, anasarca, severe anemia, and pulmonary involvement. Published guidelines (1) indicate the association of anti-interleukin-6 Siltuximab and steroids as first-line therapy for iMCD. In Siltuximab refractory patients, Tocilizumab and Rituximab are indicated, respectively, as second- and third-line therapy. Nonetheless, a large proportion of patients still do not respond to therapies. Here, we report two real-life iMCD cases, with different presentation, clinical course and response to Siltuximab.
Case n. 1 presentation
The first case is a 50-years-old Caucasian male hospitalized for Fever of Unknown Origin (FUO) persisting for one month. He daily presented fever till 39.5 °C, associated with nocturnal diaphoresis, asthenia and chills. His initial blood tests showed mild anemia (11 g/dL), normal platelet count (250 k/mL) and leukocytosis (12800 /mL) with neutrophilia and monocytosis. Inflammation markers were elevated (C-reactive protein, CRP, 132 mg/L, erythrocyte sedimentation rate, ESR, 89 mm/h) and slight hypoalbuminemia was found (3.4 g/dL). Blood culture and serological tests excluded the most frequent infections. A whole-body computed tomography (CT) showed small, contrast-enhancing, peri-pancreatic (short axis diameter 10 mm) and retrocaval adenopathies (maximum size 16 x 11 mm), with a maximum fluorodeoxyglucose (FDG) standard uptake value (SUVmax) of 7.1 at positron emission tomography (PET) scan (Fig. 1a). Bone marrow biopsy showed non-necrotizing epithelioid granulomas, as well as an excess of interstitial and perivascular polyclonal plasma cells (about 15%). To address diagnosis, retrocaval lymph nodes were surgically resected. The pathological examination indicated the presence of vascular plasma cells proliferation and expansion along with focal aspects of follicular regression (Fig. 1b, c), concluding for a compatible diagnosis of “HHV-8/HIV negative iMCD, of uncertain histopathological classification”, thus neither clearly attributable to the Hyalino Vascular, nor Plasmacytic nor Mixed subtype. IL-6 resulted elevated (76 ng/mL). According to consensus diagnostic criteria (2), a diagnosis of iMCD was established. Furthermore, the iMCD was classified as nonsevere (1), since patient did not present compromised performance status, renal dysfunction, anasarca, severe anemia or pulmonary involvement (1). Consequently, high-dose steroid therapy was administered for one week (prednisone 1 mg/Kg die) and Siltuximab (11 mg/kg every 3 weeks) was started, with rapid improvement of systemic symptoms and laboratory parameters. Computed tomography (CT) scan performed after 6 months of anti-IL-6 therapy indicated a complete regression of all previously reported adenopathies. As we report, patient is still receiving Siltuximab every 3 weeks maintaining a good clinical response.Fig. 1 Imaging and pathological findings of iMCD case 1 and case 2. Case 1 CT/PET-scan examination: contrast-enhancing peri-pancreatic and retrocaval adenopathies (a); Case 1 formalin-fixed paraffin-embedded (FFPE) lymph node: follicular regression (hematoxylin and eosin [H&E] staining, b) and plasmacytosis (CD138 staining, c). Case 2 FFPE lymph node (H&E staining, d): germinal center fragmentation (Giemsa staining, e); plasmacytosis with light chains impaired ratio (kappa staining, f). Case 2 bone marrow biopsy showing reactive plasmacytosis (CD138 staining, g). PET: computed tomography/positron emission tomography; FFPE tissue: Formalin-Fixed Paraffin-Embedded tissue; iMCD: Idiopathic multicentric Castleman disease; H&E: Hematoxylin and eosin
Case n. 2 presentation
The second case is a 49-years-old Caucasian, non-smoker, male acceded to hospital for systemic lymphadenopathy. Initially, blood tests showed increase of erythrocyte sedimentation rate (ESR, 95 mm/h) and hypergammaglobulinemia (IgG > 3000 mg/dL). Medical history was not relevant. Serological tests excluded HIV, Hepatitis C and Epstein-Barr virus. To direct diagnosis, mandibular-angle lymph node was biopsied. Pathological examination (Fig. 1d, f) showed germinal centres fragmentation, plasmacytosis (cytoplasmatic light chains kappa to lambda ratio 5:1) and HHV-8 negativity, suggesting a diagnosis compatible with HHV-8/HIV negative iMCD, plasmacytic variant. Given the absence of systemic symptoms and organ disfunction, the iMCD was classified as nonsevere (1) and the watch and wait (W&W) strategy was adopted.
After three-years of W&W, low-grade fever, malaise, asthenia and severe, diffuse, arthromyalgia occurred. Blood tests showed mild anemia (Hb 12.8 g/dL), normal platelet count (408k /ml), normal lactate dehydrogenase (221 mU/ml), albumin in range (3.7 g/dL), CRP increase (25 mg/L) and hypergammaglobulinemia (IgG 3412 mg/dL). Bone marrow biopsy pathological examination showed trilinear hyperplasia, reactive plasmacytosis (Fig. 1g) and mild excess of cytotoxic lymphocytes. The whole-body computed tomography scan indicated the presence of multiple supra-diaphragmatic and infra-diaphragmatic adenopathies (respectively maximum size, 26 mm × 10 mm and 25 × 20 mm). As next step, PET-scan (also recommended by rheumatologist in order to exclude vasculitis) was performed, confirming a moderate FDG SUV increase in mediastinal, axillary, retro-pectoral lymph nodes (maximum SUV 3.5). IL-6 resulted strongly increased (441 ng/mL). At that time Siltuximab was not yet approved for iMCD treatment in Italy. For this reason, in order to control symptoms, after steroid-based therapy failure patient received 4 cycles of Rituximab (375 mg/mq) and Etoposide (150 mg/m2) administered every week, without significant response. Therefore, 3 cycles of Siltuximab 11 mg/Kg were administered every 3 weeks (in the context of named patient program (3)), but neither clinical nor laboratory improvement was observed. For this reason, after one month, a twice-weekly Tocilizumab 8 mg/Kg administration was performed for 16 months, but patient showed only mild laboratory improvement and no regression of symptoms nor of adenopathies was observed. Afterwards, Intravenous immunoglobulin (IVIG) 25 g/die infusion for 5 days was attempted without results, as well as a further therapeutic effort with Cyclosporine (CsA, target 100–200 mcg/L) associated to Tocilizumab for six months. Since persistence of symptoms, firstly Sirolimus (target 12–20 ng/ml) for 5 months, then the anti-Interleukin-1 (anti-IL-1) Anakinra at a dose of 100 mg/die for 2 months, and then Siltuximab 11 mg/Kg again for 3 months were administered, but no improvement emerged. As we report, inflammatory syndrome and arthromyalgia are still not controlled. For this reason, since a recent lymph node biopsy confirmed iMCD diagnosis, patient has received thalidomide, cyclophosphamide and prednisone association therapy (4). Despite this, after 5 months of treatment, the association therapy was discontinued since no clinical improvement was observed.
Discussion and conclusions
The two previously reported cases coming from our hospital real-life are coherent with the evidences that IL-6 blockade is safe and, at least in 30–40% of iMCD patients, is effective (5). Conversely, despite considerable progress made in iMCD knowledge in recent years, patients not responding to IL-6 blockade often lack an effective therapy. Hopely, for IL-6 blockade refractory patients, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling (NCT03933904 trial) (6) or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone (4). In conclusion, Siltuximab is the first on label drug for iMCD frontline treatment; despite being effective and very well manageable, further efforts are required to treat that considerable part of patients who still do not respond to it.
Abbreviations
CD Castleman disease
iMCD Idiopathic multicentric Castleman disease
IL-6 Interleukin-6
FUO Fever of Unknown Origin
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
CT Computed tomography
HIV Human immunodeficiency virus
HHV-8 Human herpesvirus 8
FDG Fluorodeoxyglucose
SUV Standard uptake value
PET Positron emission tomography
W&W Watch and wait
IVIG Intravenous immunoglobulin
CsA Cyclosporine A
IL-1 Interleukin-1
Acknowledgements
The Authors would like to thank patients and their families. Moreover, Dr. Luca Molinaro (Pathologist), Dr Francesca Giunta and Dr Costanza Bachi (Nuclear Doctors) for their precious assistance in manuscript writing.
Authors' contributions
SF and SR contributed to write the manuscript. All authors read and approved the final manuscript.
Funding
None
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
SF: EUSAPharma (advisory board, speakers honoraria); SR: the author declares that he has no competing interests;
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ANAKINRA, CYCLOPHOSPHAMIDE, CYCLOSPORINE, ETOPOSIDE, IMMUNE GLOBULIN NOS, PREDNISONE, RITUXIMAB, SILTUXIMAB, SIROLIMUS, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33676575 | 19,554,682 | 2021-03-07 |
What was the dosage of drug 'ANAKINRA'? | Dichotomic response to interleukin-6 blockade in idiopathic multicentric Castleman disease: two case reports.
BACKGROUND
Human herpervirus-8/human immunodeficiency virus negative Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder sustained by a pro-inflammatory condition of hypercytokinemia mostly mediated by Interleukin-6 (IL-6). According to iMCD consensus guidelines, anti-IL-6 blockade should be the first-line therapy for iMCD. However, despite the existing therapeutic alternatives, a large proportion of iMCD patients still lacks an effective therapy.
METHODS
Here, we report two real-life iMCD cases with a different response to IL-6 blockade. The first presented patient obtained a prompt resolution of symptoms and a complete regression of adenopathies after IL-6 blockade therapy administration. Conversely, the second patient did not respond neither to Rituximab and Etoposide association nor to IL-6 blockade therapy (both Siltuximab and Tocilizumab). Furthermore, Intravenous immunoglobulin, Cyclosporine A, Sirolimus and anti-Interleukin-1 Anakinra were all attempted without any results. Since no treatment was successful, after a further confirmation of iMCD diagnosis by a second lymph node biopsy, patient has been candidate for thalidomide, cyclophosphamide and prednisone association therapy.
CONCLUSIONS
The iMCD cases we reported are coherent with the evidences that IL-6 blockade is a safe and an effective therapy for iMCD. Despite this, more than half of patients do not respond to anti IL-6 drugs. In such cases, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone. However, the two reported iMCD cases, confirm the need to more deeply investigate iMCD pathogenesis and to better dissect the heterogeneity of the disease in order to develop novel, effective therapeutic strategies.
Background
Castleman disease (CD) consists of an uncommon series of lymphoproliferative disorders comprehending several subsets. Among them, human herpervirus-8/human immunodeficiency virus (HHV-8/HIV) negative Idiopathic multicentric Castleman disease (iMCD) still remains one of the less properly understood subset(1). iMCD onset may include manifestations such as multiple lymphadenopathies, hepatosplenomegaly, cytopenias, and organ dysfunction. Furthermore, iMCD is classified into two categories (nonsevere or severe) according to Castleman disease collaborative network (CDCN) severity criteria based on patient performance status and organ dysfunction including renal disfunction, anasarca, severe anemia, and pulmonary involvement. Published guidelines (1) indicate the association of anti-interleukin-6 Siltuximab and steroids as first-line therapy for iMCD. In Siltuximab refractory patients, Tocilizumab and Rituximab are indicated, respectively, as second- and third-line therapy. Nonetheless, a large proportion of patients still do not respond to therapies. Here, we report two real-life iMCD cases, with different presentation, clinical course and response to Siltuximab.
Case n. 1 presentation
The first case is a 50-years-old Caucasian male hospitalized for Fever of Unknown Origin (FUO) persisting for one month. He daily presented fever till 39.5 °C, associated with nocturnal diaphoresis, asthenia and chills. His initial blood tests showed mild anemia (11 g/dL), normal platelet count (250 k/mL) and leukocytosis (12800 /mL) with neutrophilia and monocytosis. Inflammation markers were elevated (C-reactive protein, CRP, 132 mg/L, erythrocyte sedimentation rate, ESR, 89 mm/h) and slight hypoalbuminemia was found (3.4 g/dL). Blood culture and serological tests excluded the most frequent infections. A whole-body computed tomography (CT) showed small, contrast-enhancing, peri-pancreatic (short axis diameter 10 mm) and retrocaval adenopathies (maximum size 16 x 11 mm), with a maximum fluorodeoxyglucose (FDG) standard uptake value (SUVmax) of 7.1 at positron emission tomography (PET) scan (Fig. 1a). Bone marrow biopsy showed non-necrotizing epithelioid granulomas, as well as an excess of interstitial and perivascular polyclonal plasma cells (about 15%). To address diagnosis, retrocaval lymph nodes were surgically resected. The pathological examination indicated the presence of vascular plasma cells proliferation and expansion along with focal aspects of follicular regression (Fig. 1b, c), concluding for a compatible diagnosis of “HHV-8/HIV negative iMCD, of uncertain histopathological classification”, thus neither clearly attributable to the Hyalino Vascular, nor Plasmacytic nor Mixed subtype. IL-6 resulted elevated (76 ng/mL). According to consensus diagnostic criteria (2), a diagnosis of iMCD was established. Furthermore, the iMCD was classified as nonsevere (1), since patient did not present compromised performance status, renal dysfunction, anasarca, severe anemia or pulmonary involvement (1). Consequently, high-dose steroid therapy was administered for one week (prednisone 1 mg/Kg die) and Siltuximab (11 mg/kg every 3 weeks) was started, with rapid improvement of systemic symptoms and laboratory parameters. Computed tomography (CT) scan performed after 6 months of anti-IL-6 therapy indicated a complete regression of all previously reported adenopathies. As we report, patient is still receiving Siltuximab every 3 weeks maintaining a good clinical response.Fig. 1 Imaging and pathological findings of iMCD case 1 and case 2. Case 1 CT/PET-scan examination: contrast-enhancing peri-pancreatic and retrocaval adenopathies (a); Case 1 formalin-fixed paraffin-embedded (FFPE) lymph node: follicular regression (hematoxylin and eosin [H&E] staining, b) and plasmacytosis (CD138 staining, c). Case 2 FFPE lymph node (H&E staining, d): germinal center fragmentation (Giemsa staining, e); plasmacytosis with light chains impaired ratio (kappa staining, f). Case 2 bone marrow biopsy showing reactive plasmacytosis (CD138 staining, g). PET: computed tomography/positron emission tomography; FFPE tissue: Formalin-Fixed Paraffin-Embedded tissue; iMCD: Idiopathic multicentric Castleman disease; H&E: Hematoxylin and eosin
Case n. 2 presentation
The second case is a 49-years-old Caucasian, non-smoker, male acceded to hospital for systemic lymphadenopathy. Initially, blood tests showed increase of erythrocyte sedimentation rate (ESR, 95 mm/h) and hypergammaglobulinemia (IgG > 3000 mg/dL). Medical history was not relevant. Serological tests excluded HIV, Hepatitis C and Epstein-Barr virus. To direct diagnosis, mandibular-angle lymph node was biopsied. Pathological examination (Fig. 1d, f) showed germinal centres fragmentation, plasmacytosis (cytoplasmatic light chains kappa to lambda ratio 5:1) and HHV-8 negativity, suggesting a diagnosis compatible with HHV-8/HIV negative iMCD, plasmacytic variant. Given the absence of systemic symptoms and organ disfunction, the iMCD was classified as nonsevere (1) and the watch and wait (W&W) strategy was adopted.
After three-years of W&W, low-grade fever, malaise, asthenia and severe, diffuse, arthromyalgia occurred. Blood tests showed mild anemia (Hb 12.8 g/dL), normal platelet count (408k /ml), normal lactate dehydrogenase (221 mU/ml), albumin in range (3.7 g/dL), CRP increase (25 mg/L) and hypergammaglobulinemia (IgG 3412 mg/dL). Bone marrow biopsy pathological examination showed trilinear hyperplasia, reactive plasmacytosis (Fig. 1g) and mild excess of cytotoxic lymphocytes. The whole-body computed tomography scan indicated the presence of multiple supra-diaphragmatic and infra-diaphragmatic adenopathies (respectively maximum size, 26 mm × 10 mm and 25 × 20 mm). As next step, PET-scan (also recommended by rheumatologist in order to exclude vasculitis) was performed, confirming a moderate FDG SUV increase in mediastinal, axillary, retro-pectoral lymph nodes (maximum SUV 3.5). IL-6 resulted strongly increased (441 ng/mL). At that time Siltuximab was not yet approved for iMCD treatment in Italy. For this reason, in order to control symptoms, after steroid-based therapy failure patient received 4 cycles of Rituximab (375 mg/mq) and Etoposide (150 mg/m2) administered every week, without significant response. Therefore, 3 cycles of Siltuximab 11 mg/Kg were administered every 3 weeks (in the context of named patient program (3)), but neither clinical nor laboratory improvement was observed. For this reason, after one month, a twice-weekly Tocilizumab 8 mg/Kg administration was performed for 16 months, but patient showed only mild laboratory improvement and no regression of symptoms nor of adenopathies was observed. Afterwards, Intravenous immunoglobulin (IVIG) 25 g/die infusion for 5 days was attempted without results, as well as a further therapeutic effort with Cyclosporine (CsA, target 100–200 mcg/L) associated to Tocilizumab for six months. Since persistence of symptoms, firstly Sirolimus (target 12–20 ng/ml) for 5 months, then the anti-Interleukin-1 (anti-IL-1) Anakinra at a dose of 100 mg/die for 2 months, and then Siltuximab 11 mg/Kg again for 3 months were administered, but no improvement emerged. As we report, inflammatory syndrome and arthromyalgia are still not controlled. For this reason, since a recent lymph node biopsy confirmed iMCD diagnosis, patient has received thalidomide, cyclophosphamide and prednisone association therapy (4). Despite this, after 5 months of treatment, the association therapy was discontinued since no clinical improvement was observed.
Discussion and conclusions
The two previously reported cases coming from our hospital real-life are coherent with the evidences that IL-6 blockade is safe and, at least in 30–40% of iMCD patients, is effective (5). Conversely, despite considerable progress made in iMCD knowledge in recent years, patients not responding to IL-6 blockade often lack an effective therapy. Hopely, for IL-6 blockade refractory patients, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling (NCT03933904 trial) (6) or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone (4). In conclusion, Siltuximab is the first on label drug for iMCD frontline treatment; despite being effective and very well manageable, further efforts are required to treat that considerable part of patients who still do not respond to it.
Abbreviations
CD Castleman disease
iMCD Idiopathic multicentric Castleman disease
IL-6 Interleukin-6
FUO Fever of Unknown Origin
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
CT Computed tomography
HIV Human immunodeficiency virus
HHV-8 Human herpesvirus 8
FDG Fluorodeoxyglucose
SUV Standard uptake value
PET Positron emission tomography
W&W Watch and wait
IVIG Intravenous immunoglobulin
CsA Cyclosporine A
IL-1 Interleukin-1
Acknowledgements
The Authors would like to thank patients and their families. Moreover, Dr. Luca Molinaro (Pathologist), Dr Francesca Giunta and Dr Costanza Bachi (Nuclear Doctors) for their precious assistance in manuscript writing.
Authors' contributions
SF and SR contributed to write the manuscript. All authors read and approved the final manuscript.
Funding
None
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
SF: EUSAPharma (advisory board, speakers honoraria); SR: the author declares that he has no competing interests;
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 100 MG/DIE | DrugDosageText | CC BY | 33676575 | 19,554,682 | 2021-03-07 |
What was the dosage of drug 'ETOPOSIDE'? | Dichotomic response to interleukin-6 blockade in idiopathic multicentric Castleman disease: two case reports.
BACKGROUND
Human herpervirus-8/human immunodeficiency virus negative Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder sustained by a pro-inflammatory condition of hypercytokinemia mostly mediated by Interleukin-6 (IL-6). According to iMCD consensus guidelines, anti-IL-6 blockade should be the first-line therapy for iMCD. However, despite the existing therapeutic alternatives, a large proportion of iMCD patients still lacks an effective therapy.
METHODS
Here, we report two real-life iMCD cases with a different response to IL-6 blockade. The first presented patient obtained a prompt resolution of symptoms and a complete regression of adenopathies after IL-6 blockade therapy administration. Conversely, the second patient did not respond neither to Rituximab and Etoposide association nor to IL-6 blockade therapy (both Siltuximab and Tocilizumab). Furthermore, Intravenous immunoglobulin, Cyclosporine A, Sirolimus and anti-Interleukin-1 Anakinra were all attempted without any results. Since no treatment was successful, after a further confirmation of iMCD diagnosis by a second lymph node biopsy, patient has been candidate for thalidomide, cyclophosphamide and prednisone association therapy.
CONCLUSIONS
The iMCD cases we reported are coherent with the evidences that IL-6 blockade is a safe and an effective therapy for iMCD. Despite this, more than half of patients do not respond to anti IL-6 drugs. In such cases, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone. However, the two reported iMCD cases, confirm the need to more deeply investigate iMCD pathogenesis and to better dissect the heterogeneity of the disease in order to develop novel, effective therapeutic strategies.
Background
Castleman disease (CD) consists of an uncommon series of lymphoproliferative disorders comprehending several subsets. Among them, human herpervirus-8/human immunodeficiency virus (HHV-8/HIV) negative Idiopathic multicentric Castleman disease (iMCD) still remains one of the less properly understood subset(1). iMCD onset may include manifestations such as multiple lymphadenopathies, hepatosplenomegaly, cytopenias, and organ dysfunction. Furthermore, iMCD is classified into two categories (nonsevere or severe) according to Castleman disease collaborative network (CDCN) severity criteria based on patient performance status and organ dysfunction including renal disfunction, anasarca, severe anemia, and pulmonary involvement. Published guidelines (1) indicate the association of anti-interleukin-6 Siltuximab and steroids as first-line therapy for iMCD. In Siltuximab refractory patients, Tocilizumab and Rituximab are indicated, respectively, as second- and third-line therapy. Nonetheless, a large proportion of patients still do not respond to therapies. Here, we report two real-life iMCD cases, with different presentation, clinical course and response to Siltuximab.
Case n. 1 presentation
The first case is a 50-years-old Caucasian male hospitalized for Fever of Unknown Origin (FUO) persisting for one month. He daily presented fever till 39.5 °C, associated with nocturnal diaphoresis, asthenia and chills. His initial blood tests showed mild anemia (11 g/dL), normal platelet count (250 k/mL) and leukocytosis (12800 /mL) with neutrophilia and monocytosis. Inflammation markers were elevated (C-reactive protein, CRP, 132 mg/L, erythrocyte sedimentation rate, ESR, 89 mm/h) and slight hypoalbuminemia was found (3.4 g/dL). Blood culture and serological tests excluded the most frequent infections. A whole-body computed tomography (CT) showed small, contrast-enhancing, peri-pancreatic (short axis diameter 10 mm) and retrocaval adenopathies (maximum size 16 x 11 mm), with a maximum fluorodeoxyglucose (FDG) standard uptake value (SUVmax) of 7.1 at positron emission tomography (PET) scan (Fig. 1a). Bone marrow biopsy showed non-necrotizing epithelioid granulomas, as well as an excess of interstitial and perivascular polyclonal plasma cells (about 15%). To address diagnosis, retrocaval lymph nodes were surgically resected. The pathological examination indicated the presence of vascular plasma cells proliferation and expansion along with focal aspects of follicular regression (Fig. 1b, c), concluding for a compatible diagnosis of “HHV-8/HIV negative iMCD, of uncertain histopathological classification”, thus neither clearly attributable to the Hyalino Vascular, nor Plasmacytic nor Mixed subtype. IL-6 resulted elevated (76 ng/mL). According to consensus diagnostic criteria (2), a diagnosis of iMCD was established. Furthermore, the iMCD was classified as nonsevere (1), since patient did not present compromised performance status, renal dysfunction, anasarca, severe anemia or pulmonary involvement (1). Consequently, high-dose steroid therapy was administered for one week (prednisone 1 mg/Kg die) and Siltuximab (11 mg/kg every 3 weeks) was started, with rapid improvement of systemic symptoms and laboratory parameters. Computed tomography (CT) scan performed after 6 months of anti-IL-6 therapy indicated a complete regression of all previously reported adenopathies. As we report, patient is still receiving Siltuximab every 3 weeks maintaining a good clinical response.Fig. 1 Imaging and pathological findings of iMCD case 1 and case 2. Case 1 CT/PET-scan examination: contrast-enhancing peri-pancreatic and retrocaval adenopathies (a); Case 1 formalin-fixed paraffin-embedded (FFPE) lymph node: follicular regression (hematoxylin and eosin [H&E] staining, b) and plasmacytosis (CD138 staining, c). Case 2 FFPE lymph node (H&E staining, d): germinal center fragmentation (Giemsa staining, e); plasmacytosis with light chains impaired ratio (kappa staining, f). Case 2 bone marrow biopsy showing reactive plasmacytosis (CD138 staining, g). PET: computed tomography/positron emission tomography; FFPE tissue: Formalin-Fixed Paraffin-Embedded tissue; iMCD: Idiopathic multicentric Castleman disease; H&E: Hematoxylin and eosin
Case n. 2 presentation
The second case is a 49-years-old Caucasian, non-smoker, male acceded to hospital for systemic lymphadenopathy. Initially, blood tests showed increase of erythrocyte sedimentation rate (ESR, 95 mm/h) and hypergammaglobulinemia (IgG > 3000 mg/dL). Medical history was not relevant. Serological tests excluded HIV, Hepatitis C and Epstein-Barr virus. To direct diagnosis, mandibular-angle lymph node was biopsied. Pathological examination (Fig. 1d, f) showed germinal centres fragmentation, plasmacytosis (cytoplasmatic light chains kappa to lambda ratio 5:1) and HHV-8 negativity, suggesting a diagnosis compatible with HHV-8/HIV negative iMCD, plasmacytic variant. Given the absence of systemic symptoms and organ disfunction, the iMCD was classified as nonsevere (1) and the watch and wait (W&W) strategy was adopted.
After three-years of W&W, low-grade fever, malaise, asthenia and severe, diffuse, arthromyalgia occurred. Blood tests showed mild anemia (Hb 12.8 g/dL), normal platelet count (408k /ml), normal lactate dehydrogenase (221 mU/ml), albumin in range (3.7 g/dL), CRP increase (25 mg/L) and hypergammaglobulinemia (IgG 3412 mg/dL). Bone marrow biopsy pathological examination showed trilinear hyperplasia, reactive plasmacytosis (Fig. 1g) and mild excess of cytotoxic lymphocytes. The whole-body computed tomography scan indicated the presence of multiple supra-diaphragmatic and infra-diaphragmatic adenopathies (respectively maximum size, 26 mm × 10 mm and 25 × 20 mm). As next step, PET-scan (also recommended by rheumatologist in order to exclude vasculitis) was performed, confirming a moderate FDG SUV increase in mediastinal, axillary, retro-pectoral lymph nodes (maximum SUV 3.5). IL-6 resulted strongly increased (441 ng/mL). At that time Siltuximab was not yet approved for iMCD treatment in Italy. For this reason, in order to control symptoms, after steroid-based therapy failure patient received 4 cycles of Rituximab (375 mg/mq) and Etoposide (150 mg/m2) administered every week, without significant response. Therefore, 3 cycles of Siltuximab 11 mg/Kg were administered every 3 weeks (in the context of named patient program (3)), but neither clinical nor laboratory improvement was observed. For this reason, after one month, a twice-weekly Tocilizumab 8 mg/Kg administration was performed for 16 months, but patient showed only mild laboratory improvement and no regression of symptoms nor of adenopathies was observed. Afterwards, Intravenous immunoglobulin (IVIG) 25 g/die infusion for 5 days was attempted without results, as well as a further therapeutic effort with Cyclosporine (CsA, target 100–200 mcg/L) associated to Tocilizumab for six months. Since persistence of symptoms, firstly Sirolimus (target 12–20 ng/ml) for 5 months, then the anti-Interleukin-1 (anti-IL-1) Anakinra at a dose of 100 mg/die for 2 months, and then Siltuximab 11 mg/Kg again for 3 months were administered, but no improvement emerged. As we report, inflammatory syndrome and arthromyalgia are still not controlled. For this reason, since a recent lymph node biopsy confirmed iMCD diagnosis, patient has received thalidomide, cyclophosphamide and prednisone association therapy (4). Despite this, after 5 months of treatment, the association therapy was discontinued since no clinical improvement was observed.
Discussion and conclusions
The two previously reported cases coming from our hospital real-life are coherent with the evidences that IL-6 blockade is safe and, at least in 30–40% of iMCD patients, is effective (5). Conversely, despite considerable progress made in iMCD knowledge in recent years, patients not responding to IL-6 blockade often lack an effective therapy. Hopely, for IL-6 blockade refractory patients, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling (NCT03933904 trial) (6) or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone (4). In conclusion, Siltuximab is the first on label drug for iMCD frontline treatment; despite being effective and very well manageable, further efforts are required to treat that considerable part of patients who still do not respond to it.
Abbreviations
CD Castleman disease
iMCD Idiopathic multicentric Castleman disease
IL-6 Interleukin-6
FUO Fever of Unknown Origin
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
CT Computed tomography
HIV Human immunodeficiency virus
HHV-8 Human herpesvirus 8
FDG Fluorodeoxyglucose
SUV Standard uptake value
PET Positron emission tomography
W&W Watch and wait
IVIG Intravenous immunoglobulin
CsA Cyclosporine A
IL-1 Interleukin-1
Acknowledgements
The Authors would like to thank patients and their families. Moreover, Dr. Luca Molinaro (Pathologist), Dr Francesca Giunta and Dr Costanza Bachi (Nuclear Doctors) for their precious assistance in manuscript writing.
Authors' contributions
SF and SR contributed to write the manuscript. All authors read and approved the final manuscript.
Funding
None
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
SF: EUSAPharma (advisory board, speakers honoraria); SR: the author declares that he has no competing interests;
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 150 MILLIGRAM/SQ. METER, QW | DrugDosageText | CC BY | 33676575 | 19,554,682 | 2021-03-07 |
What was the dosage of drug 'IMMUNE GLOBULIN NOS'? | Dichotomic response to interleukin-6 blockade in idiopathic multicentric Castleman disease: two case reports.
BACKGROUND
Human herpervirus-8/human immunodeficiency virus negative Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder sustained by a pro-inflammatory condition of hypercytokinemia mostly mediated by Interleukin-6 (IL-6). According to iMCD consensus guidelines, anti-IL-6 blockade should be the first-line therapy for iMCD. However, despite the existing therapeutic alternatives, a large proportion of iMCD patients still lacks an effective therapy.
METHODS
Here, we report two real-life iMCD cases with a different response to IL-6 blockade. The first presented patient obtained a prompt resolution of symptoms and a complete regression of adenopathies after IL-6 blockade therapy administration. Conversely, the second patient did not respond neither to Rituximab and Etoposide association nor to IL-6 blockade therapy (both Siltuximab and Tocilizumab). Furthermore, Intravenous immunoglobulin, Cyclosporine A, Sirolimus and anti-Interleukin-1 Anakinra were all attempted without any results. Since no treatment was successful, after a further confirmation of iMCD diagnosis by a second lymph node biopsy, patient has been candidate for thalidomide, cyclophosphamide and prednisone association therapy.
CONCLUSIONS
The iMCD cases we reported are coherent with the evidences that IL-6 blockade is a safe and an effective therapy for iMCD. Despite this, more than half of patients do not respond to anti IL-6 drugs. In such cases, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone. However, the two reported iMCD cases, confirm the need to more deeply investigate iMCD pathogenesis and to better dissect the heterogeneity of the disease in order to develop novel, effective therapeutic strategies.
Background
Castleman disease (CD) consists of an uncommon series of lymphoproliferative disorders comprehending several subsets. Among them, human herpervirus-8/human immunodeficiency virus (HHV-8/HIV) negative Idiopathic multicentric Castleman disease (iMCD) still remains one of the less properly understood subset(1). iMCD onset may include manifestations such as multiple lymphadenopathies, hepatosplenomegaly, cytopenias, and organ dysfunction. Furthermore, iMCD is classified into two categories (nonsevere or severe) according to Castleman disease collaborative network (CDCN) severity criteria based on patient performance status and organ dysfunction including renal disfunction, anasarca, severe anemia, and pulmonary involvement. Published guidelines (1) indicate the association of anti-interleukin-6 Siltuximab and steroids as first-line therapy for iMCD. In Siltuximab refractory patients, Tocilizumab and Rituximab are indicated, respectively, as second- and third-line therapy. Nonetheless, a large proportion of patients still do not respond to therapies. Here, we report two real-life iMCD cases, with different presentation, clinical course and response to Siltuximab.
Case n. 1 presentation
The first case is a 50-years-old Caucasian male hospitalized for Fever of Unknown Origin (FUO) persisting for one month. He daily presented fever till 39.5 °C, associated with nocturnal diaphoresis, asthenia and chills. His initial blood tests showed mild anemia (11 g/dL), normal platelet count (250 k/mL) and leukocytosis (12800 /mL) with neutrophilia and monocytosis. Inflammation markers were elevated (C-reactive protein, CRP, 132 mg/L, erythrocyte sedimentation rate, ESR, 89 mm/h) and slight hypoalbuminemia was found (3.4 g/dL). Blood culture and serological tests excluded the most frequent infections. A whole-body computed tomography (CT) showed small, contrast-enhancing, peri-pancreatic (short axis diameter 10 mm) and retrocaval adenopathies (maximum size 16 x 11 mm), with a maximum fluorodeoxyglucose (FDG) standard uptake value (SUVmax) of 7.1 at positron emission tomography (PET) scan (Fig. 1a). Bone marrow biopsy showed non-necrotizing epithelioid granulomas, as well as an excess of interstitial and perivascular polyclonal plasma cells (about 15%). To address diagnosis, retrocaval lymph nodes were surgically resected. The pathological examination indicated the presence of vascular plasma cells proliferation and expansion along with focal aspects of follicular regression (Fig. 1b, c), concluding for a compatible diagnosis of “HHV-8/HIV negative iMCD, of uncertain histopathological classification”, thus neither clearly attributable to the Hyalino Vascular, nor Plasmacytic nor Mixed subtype. IL-6 resulted elevated (76 ng/mL). According to consensus diagnostic criteria (2), a diagnosis of iMCD was established. Furthermore, the iMCD was classified as nonsevere (1), since patient did not present compromised performance status, renal dysfunction, anasarca, severe anemia or pulmonary involvement (1). Consequently, high-dose steroid therapy was administered for one week (prednisone 1 mg/Kg die) and Siltuximab (11 mg/kg every 3 weeks) was started, with rapid improvement of systemic symptoms and laboratory parameters. Computed tomography (CT) scan performed after 6 months of anti-IL-6 therapy indicated a complete regression of all previously reported adenopathies. As we report, patient is still receiving Siltuximab every 3 weeks maintaining a good clinical response.Fig. 1 Imaging and pathological findings of iMCD case 1 and case 2. Case 1 CT/PET-scan examination: contrast-enhancing peri-pancreatic and retrocaval adenopathies (a); Case 1 formalin-fixed paraffin-embedded (FFPE) lymph node: follicular regression (hematoxylin and eosin [H&E] staining, b) and plasmacytosis (CD138 staining, c). Case 2 FFPE lymph node (H&E staining, d): germinal center fragmentation (Giemsa staining, e); plasmacytosis with light chains impaired ratio (kappa staining, f). Case 2 bone marrow biopsy showing reactive plasmacytosis (CD138 staining, g). PET: computed tomography/positron emission tomography; FFPE tissue: Formalin-Fixed Paraffin-Embedded tissue; iMCD: Idiopathic multicentric Castleman disease; H&E: Hematoxylin and eosin
Case n. 2 presentation
The second case is a 49-years-old Caucasian, non-smoker, male acceded to hospital for systemic lymphadenopathy. Initially, blood tests showed increase of erythrocyte sedimentation rate (ESR, 95 mm/h) and hypergammaglobulinemia (IgG > 3000 mg/dL). Medical history was not relevant. Serological tests excluded HIV, Hepatitis C and Epstein-Barr virus. To direct diagnosis, mandibular-angle lymph node was biopsied. Pathological examination (Fig. 1d, f) showed germinal centres fragmentation, plasmacytosis (cytoplasmatic light chains kappa to lambda ratio 5:1) and HHV-8 negativity, suggesting a diagnosis compatible with HHV-8/HIV negative iMCD, plasmacytic variant. Given the absence of systemic symptoms and organ disfunction, the iMCD was classified as nonsevere (1) and the watch and wait (W&W) strategy was adopted.
After three-years of W&W, low-grade fever, malaise, asthenia and severe, diffuse, arthromyalgia occurred. Blood tests showed mild anemia (Hb 12.8 g/dL), normal platelet count (408k /ml), normal lactate dehydrogenase (221 mU/ml), albumin in range (3.7 g/dL), CRP increase (25 mg/L) and hypergammaglobulinemia (IgG 3412 mg/dL). Bone marrow biopsy pathological examination showed trilinear hyperplasia, reactive plasmacytosis (Fig. 1g) and mild excess of cytotoxic lymphocytes. The whole-body computed tomography scan indicated the presence of multiple supra-diaphragmatic and infra-diaphragmatic adenopathies (respectively maximum size, 26 mm × 10 mm and 25 × 20 mm). As next step, PET-scan (also recommended by rheumatologist in order to exclude vasculitis) was performed, confirming a moderate FDG SUV increase in mediastinal, axillary, retro-pectoral lymph nodes (maximum SUV 3.5). IL-6 resulted strongly increased (441 ng/mL). At that time Siltuximab was not yet approved for iMCD treatment in Italy. For this reason, in order to control symptoms, after steroid-based therapy failure patient received 4 cycles of Rituximab (375 mg/mq) and Etoposide (150 mg/m2) administered every week, without significant response. Therefore, 3 cycles of Siltuximab 11 mg/Kg were administered every 3 weeks (in the context of named patient program (3)), but neither clinical nor laboratory improvement was observed. For this reason, after one month, a twice-weekly Tocilizumab 8 mg/Kg administration was performed for 16 months, but patient showed only mild laboratory improvement and no regression of symptoms nor of adenopathies was observed. Afterwards, Intravenous immunoglobulin (IVIG) 25 g/die infusion for 5 days was attempted without results, as well as a further therapeutic effort with Cyclosporine (CsA, target 100–200 mcg/L) associated to Tocilizumab for six months. Since persistence of symptoms, firstly Sirolimus (target 12–20 ng/ml) for 5 months, then the anti-Interleukin-1 (anti-IL-1) Anakinra at a dose of 100 mg/die for 2 months, and then Siltuximab 11 mg/Kg again for 3 months were administered, but no improvement emerged. As we report, inflammatory syndrome and arthromyalgia are still not controlled. For this reason, since a recent lymph node biopsy confirmed iMCD diagnosis, patient has received thalidomide, cyclophosphamide and prednisone association therapy (4). Despite this, after 5 months of treatment, the association therapy was discontinued since no clinical improvement was observed.
Discussion and conclusions
The two previously reported cases coming from our hospital real-life are coherent with the evidences that IL-6 blockade is safe and, at least in 30–40% of iMCD patients, is effective (5). Conversely, despite considerable progress made in iMCD knowledge in recent years, patients not responding to IL-6 blockade often lack an effective therapy. Hopely, for IL-6 blockade refractory patients, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling (NCT03933904 trial) (6) or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone (4). In conclusion, Siltuximab is the first on label drug for iMCD frontline treatment; despite being effective and very well manageable, further efforts are required to treat that considerable part of patients who still do not respond to it.
Abbreviations
CD Castleman disease
iMCD Idiopathic multicentric Castleman disease
IL-6 Interleukin-6
FUO Fever of Unknown Origin
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
CT Computed tomography
HIV Human immunodeficiency virus
HHV-8 Human herpesvirus 8
FDG Fluorodeoxyglucose
SUV Standard uptake value
PET Positron emission tomography
W&W Watch and wait
IVIG Intravenous immunoglobulin
CsA Cyclosporine A
IL-1 Interleukin-1
Acknowledgements
The Authors would like to thank patients and their families. Moreover, Dr. Luca Molinaro (Pathologist), Dr Francesca Giunta and Dr Costanza Bachi (Nuclear Doctors) for their precious assistance in manuscript writing.
Authors' contributions
SF and SR contributed to write the manuscript. All authors read and approved the final manuscript.
Funding
None
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
SF: EUSAPharma (advisory board, speakers honoraria); SR: the author declares that he has no competing interests;
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 25 G/DIE | DrugDosageText | CC BY | 33676575 | 19,554,682 | 2021-03-07 |
What was the dosage of drug 'RITUXIMAB'? | Dichotomic response to interleukin-6 blockade in idiopathic multicentric Castleman disease: two case reports.
BACKGROUND
Human herpervirus-8/human immunodeficiency virus negative Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder sustained by a pro-inflammatory condition of hypercytokinemia mostly mediated by Interleukin-6 (IL-6). According to iMCD consensus guidelines, anti-IL-6 blockade should be the first-line therapy for iMCD. However, despite the existing therapeutic alternatives, a large proportion of iMCD patients still lacks an effective therapy.
METHODS
Here, we report two real-life iMCD cases with a different response to IL-6 blockade. The first presented patient obtained a prompt resolution of symptoms and a complete regression of adenopathies after IL-6 blockade therapy administration. Conversely, the second patient did not respond neither to Rituximab and Etoposide association nor to IL-6 blockade therapy (both Siltuximab and Tocilizumab). Furthermore, Intravenous immunoglobulin, Cyclosporine A, Sirolimus and anti-Interleukin-1 Anakinra were all attempted without any results. Since no treatment was successful, after a further confirmation of iMCD diagnosis by a second lymph node biopsy, patient has been candidate for thalidomide, cyclophosphamide and prednisone association therapy.
CONCLUSIONS
The iMCD cases we reported are coherent with the evidences that IL-6 blockade is a safe and an effective therapy for iMCD. Despite this, more than half of patients do not respond to anti IL-6 drugs. In such cases, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone. However, the two reported iMCD cases, confirm the need to more deeply investigate iMCD pathogenesis and to better dissect the heterogeneity of the disease in order to develop novel, effective therapeutic strategies.
Background
Castleman disease (CD) consists of an uncommon series of lymphoproliferative disorders comprehending several subsets. Among them, human herpervirus-8/human immunodeficiency virus (HHV-8/HIV) negative Idiopathic multicentric Castleman disease (iMCD) still remains one of the less properly understood subset(1). iMCD onset may include manifestations such as multiple lymphadenopathies, hepatosplenomegaly, cytopenias, and organ dysfunction. Furthermore, iMCD is classified into two categories (nonsevere or severe) according to Castleman disease collaborative network (CDCN) severity criteria based on patient performance status and organ dysfunction including renal disfunction, anasarca, severe anemia, and pulmonary involvement. Published guidelines (1) indicate the association of anti-interleukin-6 Siltuximab and steroids as first-line therapy for iMCD. In Siltuximab refractory patients, Tocilizumab and Rituximab are indicated, respectively, as second- and third-line therapy. Nonetheless, a large proportion of patients still do not respond to therapies. Here, we report two real-life iMCD cases, with different presentation, clinical course and response to Siltuximab.
Case n. 1 presentation
The first case is a 50-years-old Caucasian male hospitalized for Fever of Unknown Origin (FUO) persisting for one month. He daily presented fever till 39.5 °C, associated with nocturnal diaphoresis, asthenia and chills. His initial blood tests showed mild anemia (11 g/dL), normal platelet count (250 k/mL) and leukocytosis (12800 /mL) with neutrophilia and monocytosis. Inflammation markers were elevated (C-reactive protein, CRP, 132 mg/L, erythrocyte sedimentation rate, ESR, 89 mm/h) and slight hypoalbuminemia was found (3.4 g/dL). Blood culture and serological tests excluded the most frequent infections. A whole-body computed tomography (CT) showed small, contrast-enhancing, peri-pancreatic (short axis diameter 10 mm) and retrocaval adenopathies (maximum size 16 x 11 mm), with a maximum fluorodeoxyglucose (FDG) standard uptake value (SUVmax) of 7.1 at positron emission tomography (PET) scan (Fig. 1a). Bone marrow biopsy showed non-necrotizing epithelioid granulomas, as well as an excess of interstitial and perivascular polyclonal plasma cells (about 15%). To address diagnosis, retrocaval lymph nodes were surgically resected. The pathological examination indicated the presence of vascular plasma cells proliferation and expansion along with focal aspects of follicular regression (Fig. 1b, c), concluding for a compatible diagnosis of “HHV-8/HIV negative iMCD, of uncertain histopathological classification”, thus neither clearly attributable to the Hyalino Vascular, nor Plasmacytic nor Mixed subtype. IL-6 resulted elevated (76 ng/mL). According to consensus diagnostic criteria (2), a diagnosis of iMCD was established. Furthermore, the iMCD was classified as nonsevere (1), since patient did not present compromised performance status, renal dysfunction, anasarca, severe anemia or pulmonary involvement (1). Consequently, high-dose steroid therapy was administered for one week (prednisone 1 mg/Kg die) and Siltuximab (11 mg/kg every 3 weeks) was started, with rapid improvement of systemic symptoms and laboratory parameters. Computed tomography (CT) scan performed after 6 months of anti-IL-6 therapy indicated a complete regression of all previously reported adenopathies. As we report, patient is still receiving Siltuximab every 3 weeks maintaining a good clinical response.Fig. 1 Imaging and pathological findings of iMCD case 1 and case 2. Case 1 CT/PET-scan examination: contrast-enhancing peri-pancreatic and retrocaval adenopathies (a); Case 1 formalin-fixed paraffin-embedded (FFPE) lymph node: follicular regression (hematoxylin and eosin [H&E] staining, b) and plasmacytosis (CD138 staining, c). Case 2 FFPE lymph node (H&E staining, d): germinal center fragmentation (Giemsa staining, e); plasmacytosis with light chains impaired ratio (kappa staining, f). Case 2 bone marrow biopsy showing reactive plasmacytosis (CD138 staining, g). PET: computed tomography/positron emission tomography; FFPE tissue: Formalin-Fixed Paraffin-Embedded tissue; iMCD: Idiopathic multicentric Castleman disease; H&E: Hematoxylin and eosin
Case n. 2 presentation
The second case is a 49-years-old Caucasian, non-smoker, male acceded to hospital for systemic lymphadenopathy. Initially, blood tests showed increase of erythrocyte sedimentation rate (ESR, 95 mm/h) and hypergammaglobulinemia (IgG > 3000 mg/dL). Medical history was not relevant. Serological tests excluded HIV, Hepatitis C and Epstein-Barr virus. To direct diagnosis, mandibular-angle lymph node was biopsied. Pathological examination (Fig. 1d, f) showed germinal centres fragmentation, plasmacytosis (cytoplasmatic light chains kappa to lambda ratio 5:1) and HHV-8 negativity, suggesting a diagnosis compatible with HHV-8/HIV negative iMCD, plasmacytic variant. Given the absence of systemic symptoms and organ disfunction, the iMCD was classified as nonsevere (1) and the watch and wait (W&W) strategy was adopted.
After three-years of W&W, low-grade fever, malaise, asthenia and severe, diffuse, arthromyalgia occurred. Blood tests showed mild anemia (Hb 12.8 g/dL), normal platelet count (408k /ml), normal lactate dehydrogenase (221 mU/ml), albumin in range (3.7 g/dL), CRP increase (25 mg/L) and hypergammaglobulinemia (IgG 3412 mg/dL). Bone marrow biopsy pathological examination showed trilinear hyperplasia, reactive plasmacytosis (Fig. 1g) and mild excess of cytotoxic lymphocytes. The whole-body computed tomography scan indicated the presence of multiple supra-diaphragmatic and infra-diaphragmatic adenopathies (respectively maximum size, 26 mm × 10 mm and 25 × 20 mm). As next step, PET-scan (also recommended by rheumatologist in order to exclude vasculitis) was performed, confirming a moderate FDG SUV increase in mediastinal, axillary, retro-pectoral lymph nodes (maximum SUV 3.5). IL-6 resulted strongly increased (441 ng/mL). At that time Siltuximab was not yet approved for iMCD treatment in Italy. For this reason, in order to control symptoms, after steroid-based therapy failure patient received 4 cycles of Rituximab (375 mg/mq) and Etoposide (150 mg/m2) administered every week, without significant response. Therefore, 3 cycles of Siltuximab 11 mg/Kg were administered every 3 weeks (in the context of named patient program (3)), but neither clinical nor laboratory improvement was observed. For this reason, after one month, a twice-weekly Tocilizumab 8 mg/Kg administration was performed for 16 months, but patient showed only mild laboratory improvement and no regression of symptoms nor of adenopathies was observed. Afterwards, Intravenous immunoglobulin (IVIG) 25 g/die infusion for 5 days was attempted without results, as well as a further therapeutic effort with Cyclosporine (CsA, target 100–200 mcg/L) associated to Tocilizumab for six months. Since persistence of symptoms, firstly Sirolimus (target 12–20 ng/ml) for 5 months, then the anti-Interleukin-1 (anti-IL-1) Anakinra at a dose of 100 mg/die for 2 months, and then Siltuximab 11 mg/Kg again for 3 months were administered, but no improvement emerged. As we report, inflammatory syndrome and arthromyalgia are still not controlled. For this reason, since a recent lymph node biopsy confirmed iMCD diagnosis, patient has received thalidomide, cyclophosphamide and prednisone association therapy (4). Despite this, after 5 months of treatment, the association therapy was discontinued since no clinical improvement was observed.
Discussion and conclusions
The two previously reported cases coming from our hospital real-life are coherent with the evidences that IL-6 blockade is safe and, at least in 30–40% of iMCD patients, is effective (5). Conversely, despite considerable progress made in iMCD knowledge in recent years, patients not responding to IL-6 blockade often lack an effective therapy. Hopely, for IL-6 blockade refractory patients, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling (NCT03933904 trial) (6) or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone (4). In conclusion, Siltuximab is the first on label drug for iMCD frontline treatment; despite being effective and very well manageable, further efforts are required to treat that considerable part of patients who still do not respond to it.
Abbreviations
CD Castleman disease
iMCD Idiopathic multicentric Castleman disease
IL-6 Interleukin-6
FUO Fever of Unknown Origin
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
CT Computed tomography
HIV Human immunodeficiency virus
HHV-8 Human herpesvirus 8
FDG Fluorodeoxyglucose
SUV Standard uptake value
PET Positron emission tomography
W&W Watch and wait
IVIG Intravenous immunoglobulin
CsA Cyclosporine A
IL-1 Interleukin-1
Acknowledgements
The Authors would like to thank patients and their families. Moreover, Dr. Luca Molinaro (Pathologist), Dr Francesca Giunta and Dr Costanza Bachi (Nuclear Doctors) for their precious assistance in manuscript writing.
Authors' contributions
SF and SR contributed to write the manuscript. All authors read and approved the final manuscript.
Funding
None
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
SF: EUSAPharma (advisory board, speakers honoraria); SR: the author declares that he has no competing interests;
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 375 MG/MQ FOUR CYCLES, CYCLICAL | DrugDosageText | CC BY | 33676575 | 19,554,682 | 2021-03-07 |
What was the dosage of drug 'TOCILIZUMAB'? | Dichotomic response to interleukin-6 blockade in idiopathic multicentric Castleman disease: two case reports.
BACKGROUND
Human herpervirus-8/human immunodeficiency virus negative Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder sustained by a pro-inflammatory condition of hypercytokinemia mostly mediated by Interleukin-6 (IL-6). According to iMCD consensus guidelines, anti-IL-6 blockade should be the first-line therapy for iMCD. However, despite the existing therapeutic alternatives, a large proportion of iMCD patients still lacks an effective therapy.
METHODS
Here, we report two real-life iMCD cases with a different response to IL-6 blockade. The first presented patient obtained a prompt resolution of symptoms and a complete regression of adenopathies after IL-6 blockade therapy administration. Conversely, the second patient did not respond neither to Rituximab and Etoposide association nor to IL-6 blockade therapy (both Siltuximab and Tocilizumab). Furthermore, Intravenous immunoglobulin, Cyclosporine A, Sirolimus and anti-Interleukin-1 Anakinra were all attempted without any results. Since no treatment was successful, after a further confirmation of iMCD diagnosis by a second lymph node biopsy, patient has been candidate for thalidomide, cyclophosphamide and prednisone association therapy.
CONCLUSIONS
The iMCD cases we reported are coherent with the evidences that IL-6 blockade is a safe and an effective therapy for iMCD. Despite this, more than half of patients do not respond to anti IL-6 drugs. In such cases, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone. However, the two reported iMCD cases, confirm the need to more deeply investigate iMCD pathogenesis and to better dissect the heterogeneity of the disease in order to develop novel, effective therapeutic strategies.
Background
Castleman disease (CD) consists of an uncommon series of lymphoproliferative disorders comprehending several subsets. Among them, human herpervirus-8/human immunodeficiency virus (HHV-8/HIV) negative Idiopathic multicentric Castleman disease (iMCD) still remains one of the less properly understood subset(1). iMCD onset may include manifestations such as multiple lymphadenopathies, hepatosplenomegaly, cytopenias, and organ dysfunction. Furthermore, iMCD is classified into two categories (nonsevere or severe) according to Castleman disease collaborative network (CDCN) severity criteria based on patient performance status and organ dysfunction including renal disfunction, anasarca, severe anemia, and pulmonary involvement. Published guidelines (1) indicate the association of anti-interleukin-6 Siltuximab and steroids as first-line therapy for iMCD. In Siltuximab refractory patients, Tocilizumab and Rituximab are indicated, respectively, as second- and third-line therapy. Nonetheless, a large proportion of patients still do not respond to therapies. Here, we report two real-life iMCD cases, with different presentation, clinical course and response to Siltuximab.
Case n. 1 presentation
The first case is a 50-years-old Caucasian male hospitalized for Fever of Unknown Origin (FUO) persisting for one month. He daily presented fever till 39.5 °C, associated with nocturnal diaphoresis, asthenia and chills. His initial blood tests showed mild anemia (11 g/dL), normal platelet count (250 k/mL) and leukocytosis (12800 /mL) with neutrophilia and monocytosis. Inflammation markers were elevated (C-reactive protein, CRP, 132 mg/L, erythrocyte sedimentation rate, ESR, 89 mm/h) and slight hypoalbuminemia was found (3.4 g/dL). Blood culture and serological tests excluded the most frequent infections. A whole-body computed tomography (CT) showed small, contrast-enhancing, peri-pancreatic (short axis diameter 10 mm) and retrocaval adenopathies (maximum size 16 x 11 mm), with a maximum fluorodeoxyglucose (FDG) standard uptake value (SUVmax) of 7.1 at positron emission tomography (PET) scan (Fig. 1a). Bone marrow biopsy showed non-necrotizing epithelioid granulomas, as well as an excess of interstitial and perivascular polyclonal plasma cells (about 15%). To address diagnosis, retrocaval lymph nodes were surgically resected. The pathological examination indicated the presence of vascular plasma cells proliferation and expansion along with focal aspects of follicular regression (Fig. 1b, c), concluding for a compatible diagnosis of “HHV-8/HIV negative iMCD, of uncertain histopathological classification”, thus neither clearly attributable to the Hyalino Vascular, nor Plasmacytic nor Mixed subtype. IL-6 resulted elevated (76 ng/mL). According to consensus diagnostic criteria (2), a diagnosis of iMCD was established. Furthermore, the iMCD was classified as nonsevere (1), since patient did not present compromised performance status, renal dysfunction, anasarca, severe anemia or pulmonary involvement (1). Consequently, high-dose steroid therapy was administered for one week (prednisone 1 mg/Kg die) and Siltuximab (11 mg/kg every 3 weeks) was started, with rapid improvement of systemic symptoms and laboratory parameters. Computed tomography (CT) scan performed after 6 months of anti-IL-6 therapy indicated a complete regression of all previously reported adenopathies. As we report, patient is still receiving Siltuximab every 3 weeks maintaining a good clinical response.Fig. 1 Imaging and pathological findings of iMCD case 1 and case 2. Case 1 CT/PET-scan examination: contrast-enhancing peri-pancreatic and retrocaval adenopathies (a); Case 1 formalin-fixed paraffin-embedded (FFPE) lymph node: follicular regression (hematoxylin and eosin [H&E] staining, b) and plasmacytosis (CD138 staining, c). Case 2 FFPE lymph node (H&E staining, d): germinal center fragmentation (Giemsa staining, e); plasmacytosis with light chains impaired ratio (kappa staining, f). Case 2 bone marrow biopsy showing reactive plasmacytosis (CD138 staining, g). PET: computed tomography/positron emission tomography; FFPE tissue: Formalin-Fixed Paraffin-Embedded tissue; iMCD: Idiopathic multicentric Castleman disease; H&E: Hematoxylin and eosin
Case n. 2 presentation
The second case is a 49-years-old Caucasian, non-smoker, male acceded to hospital for systemic lymphadenopathy. Initially, blood tests showed increase of erythrocyte sedimentation rate (ESR, 95 mm/h) and hypergammaglobulinemia (IgG > 3000 mg/dL). Medical history was not relevant. Serological tests excluded HIV, Hepatitis C and Epstein-Barr virus. To direct diagnosis, mandibular-angle lymph node was biopsied. Pathological examination (Fig. 1d, f) showed germinal centres fragmentation, plasmacytosis (cytoplasmatic light chains kappa to lambda ratio 5:1) and HHV-8 negativity, suggesting a diagnosis compatible with HHV-8/HIV negative iMCD, plasmacytic variant. Given the absence of systemic symptoms and organ disfunction, the iMCD was classified as nonsevere (1) and the watch and wait (W&W) strategy was adopted.
After three-years of W&W, low-grade fever, malaise, asthenia and severe, diffuse, arthromyalgia occurred. Blood tests showed mild anemia (Hb 12.8 g/dL), normal platelet count (408k /ml), normal lactate dehydrogenase (221 mU/ml), albumin in range (3.7 g/dL), CRP increase (25 mg/L) and hypergammaglobulinemia (IgG 3412 mg/dL). Bone marrow biopsy pathological examination showed trilinear hyperplasia, reactive plasmacytosis (Fig. 1g) and mild excess of cytotoxic lymphocytes. The whole-body computed tomography scan indicated the presence of multiple supra-diaphragmatic and infra-diaphragmatic adenopathies (respectively maximum size, 26 mm × 10 mm and 25 × 20 mm). As next step, PET-scan (also recommended by rheumatologist in order to exclude vasculitis) was performed, confirming a moderate FDG SUV increase in mediastinal, axillary, retro-pectoral lymph nodes (maximum SUV 3.5). IL-6 resulted strongly increased (441 ng/mL). At that time Siltuximab was not yet approved for iMCD treatment in Italy. For this reason, in order to control symptoms, after steroid-based therapy failure patient received 4 cycles of Rituximab (375 mg/mq) and Etoposide (150 mg/m2) administered every week, without significant response. Therefore, 3 cycles of Siltuximab 11 mg/Kg were administered every 3 weeks (in the context of named patient program (3)), but neither clinical nor laboratory improvement was observed. For this reason, after one month, a twice-weekly Tocilizumab 8 mg/Kg administration was performed for 16 months, but patient showed only mild laboratory improvement and no regression of symptoms nor of adenopathies was observed. Afterwards, Intravenous immunoglobulin (IVIG) 25 g/die infusion for 5 days was attempted without results, as well as a further therapeutic effort with Cyclosporine (CsA, target 100–200 mcg/L) associated to Tocilizumab for six months. Since persistence of symptoms, firstly Sirolimus (target 12–20 ng/ml) for 5 months, then the anti-Interleukin-1 (anti-IL-1) Anakinra at a dose of 100 mg/die for 2 months, and then Siltuximab 11 mg/Kg again for 3 months were administered, but no improvement emerged. As we report, inflammatory syndrome and arthromyalgia are still not controlled. For this reason, since a recent lymph node biopsy confirmed iMCD diagnosis, patient has received thalidomide, cyclophosphamide and prednisone association therapy (4). Despite this, after 5 months of treatment, the association therapy was discontinued since no clinical improvement was observed.
Discussion and conclusions
The two previously reported cases coming from our hospital real-life are coherent with the evidences that IL-6 blockade is safe and, at least in 30–40% of iMCD patients, is effective (5). Conversely, despite considerable progress made in iMCD knowledge in recent years, patients not responding to IL-6 blockade often lack an effective therapy. Hopely, for IL-6 blockade refractory patients, therapeutic alternatives could be represented by Sirolimus, targeting PI3K/AKT/mTOR signaling (NCT03933904 trial) (6) or by associations of conventional drugs such as thalidomide, cyclophosphamide and prednisone (4). In conclusion, Siltuximab is the first on label drug for iMCD frontline treatment; despite being effective and very well manageable, further efforts are required to treat that considerable part of patients who still do not respond to it.
Abbreviations
CD Castleman disease
iMCD Idiopathic multicentric Castleman disease
IL-6 Interleukin-6
FUO Fever of Unknown Origin
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
CT Computed tomography
HIV Human immunodeficiency virus
HHV-8 Human herpesvirus 8
FDG Fluorodeoxyglucose
SUV Standard uptake value
PET Positron emission tomography
W&W Watch and wait
IVIG Intravenous immunoglobulin
CsA Cyclosporine A
IL-1 Interleukin-1
Acknowledgements
The Authors would like to thank patients and their families. Moreover, Dr. Luca Molinaro (Pathologist), Dr Francesca Giunta and Dr Costanza Bachi (Nuclear Doctors) for their precious assistance in manuscript writing.
Authors' contributions
SF and SR contributed to write the manuscript. All authors read and approved the final manuscript.
Funding
None
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
SF: EUSAPharma (advisory board, speakers honoraria); SR: the author declares that he has no competing interests;
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 8 MILLIGRAM/KILOGRAM, BIWEEKLY | DrugDosageText | CC BY | 33676575 | 19,554,682 | 2021-03-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Constipation'. | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | BORTEZOMIB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-SA | 33677871 | 19,043,265 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | BORTEZOMIB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-SA | 33677871 | 19,043,265 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug intolerance'. | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | BORTEZOMIB, CYCLOPHOSPHAMIDE, DEXAMETHASONE, LENALIDOMIDE | DrugsGivenReaction | CC BY-NC-SA | 33677871 | 19,093,532 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Inappropriate antidiuretic hormone secretion'. | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | BORTEZOMIB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-SA | 33677871 | 19,207,262 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neurotoxicity'. | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | BORTEZOMIB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-SA | 33677871 | 19,207,262 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | BORTEZOMIB, DEXAMETHASONE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-SA | 33677871 | 19,207,262 | 2021-01-14 |
What was the dosage of drug 'BORTEZOMIB'? | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | UNKNOWN | DrugDosageText | CC BY-NC-SA | 33677871 | 19,207,262 | 2021-01-14 |
What was the outcome of reaction 'Hyponatraemia'? | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | Recovered | ReactionOutcome | CC BY-NC-SA | 33677871 | 19,093,532 | 2021-01-14 |
What was the outcome of reaction 'Inappropriate antidiuretic hormone secretion'? | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | Recovered | ReactionOutcome | CC BY-NC-SA | 33677871 | 19,207,262 | 2021-01-14 |
What was the outcome of reaction 'Neurotoxicity'? | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | Recovered | ReactionOutcome | CC BY-NC-SA | 33677871 | 19,207,262 | 2021-01-14 |
What was the outcome of reaction 'Pyrexia'? | Central nervous system toxicity caused by bortezomib: five case reports and a review of literature.
Objective: To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib. Methods: This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature. Results: CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib. Conclusion: Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.
第一代蛋白酶体抑制剂硼替佐米的应用在多发性骨髓瘤（MM）的治疗进展中具有划时代的意义，并在临床上得到了广泛应用[1]。硼替佐米最常见的不良反应为周围神经炎、胃肠道症状和血小板减少[2]，而累及中枢神经系统（CNS）的毒性相对少见。硼替佐米CNS毒性的相关报道比较少，既往文献报道的表现形式主要有两种：抗利尿不当综合征（syndrome of inappropriate antidiuresis，SIAD）和可逆性后部脑病综合征（posterior reversible encephalopathy syndrome，PRES）。我们在600余例接受硼替佐米治疗的患者中共发现5例由硼替佐米引起的CNS毒性患者，现结合文献复习，报道如下。
病例资料
例1，男，53岁，2018年6月确诊为MM，2018年9月4日在接受第3个疗程VDD（硼替佐米+多柔比星脂质体+地塞米松）方案的第2次硼替佐米治疗后出现便秘腹泻交替，查血钠130 mmol/L，予停用硼替佐米。2018年9月8日患者出现发热，体温38.5 °C，无畏寒、寒战，精神状态差。查体：无汗，双侧瞳孔对光反射迟钝，球结膜水肿。血常规：WBC 5.21×109/L，HGB 113 g/L，PLT 18×109/L。血钠109.9 mmol/L，皮质醇及甲状腺功能正常。予补钠、退热、抗感染后患者体温仍高（38.2～38.5°C），无汗，嗜睡，完善头胸腹CT未见异常。2018年9月12日晚患者出现间断意识障碍，血钠99.8 mmol/L，尿钠>40 mmol/L，考虑SIAD，予限液、托伐普坦片等治疗后患者次日意识恢复，后续患者汗出热退，血钠逐渐上升至136 mmol/L。患者于院外停止化疗，未再出现类似情况。
例2，女，73岁，因MM进展参与DVd[达雷妥尤单抗（Dara）+硼替佐米+地塞米松]方案的临床试验，患者接受第5个疗程第8天的Vd（硼替佐米+地塞米松）方案治疗，3 d后出现高热（体温39.5 °C），伴双手不自主抖动，周身无汗，血压126/79 mmHg（1 mmHg＝0.133 kPa）。血常规：WBC 9.92×109/L，HGB 135 g/L，PLT 68×109/L；血钠124.4 mmol/L。胸腹CT检查未见明显感染灶。予补钠、退热、抗感染治疗后患者体温仍高（38.0～39.5 °C）。5 d后患者出现神志不清，答不切题，体温39.9 °C，复查PLT 15×109/L，血钠122 mmol/L，24 h尿钠24.73 mmol/L（<40 mmol/L，暂不支持SIAD的诊断）。血培养、G试验、GM试验均为阴性。头CT：双侧半卵圆中心白质密度减低。患者应用硼替佐米后相继出现周围神经病加重、中枢性发热、意识障碍及顽固性低钠血症，考虑硼替佐米所致CNS毒性可能性大，嘱暂停化疗，物理降温。患者补钠后血钠仍低，予托伐普坦治疗，后血钠逐渐恢复至133 mmol/L，体温及意识也逐渐恢复。
例3，男，62岁，2020年5月因MM进展入院，予Dara+VRD（硼替佐米+来那度胺+地塞米松）方案化疗，因患者PLT低（24×109/L），硼替佐米推迟2 d应用。患者注射第1针硼替佐米2 d后出现发热（体温38.5 °C），无畏寒、寒战，血常规：WBC 2.19×109/L，HGB 61 g/L，PLT 17×109/L；血钠127.2 mmol/L。予积极抗感染和退热治疗后，患者仍发热（体温38～38.5 °C），周身无汗，GM实验、G实验和血培养均阴性。考虑不除外硼替佐米相关CNS毒性，暂停化疗，予冰袋物理降温，高渗盐水输注。3 d后患者体温略下降（37.5～38 °C），仍无汗，仍有低钠血症（血钠127～132 mmol/L），嘱加用托伐普坦口服治疗，后患者血钠逐渐上升至正常。约1周后患者开始出汗，体温逐渐降至正常。后改予Dara+IRD（伊沙佐米+来那度胺+地塞米松）方案治疗，未再出现发热及低钠血症。
例4，女，62岁，2019年4月确诊MM，2019年9月24日完成第6周期VRD方案的第3次硼替佐米注射，25日出现腹泻伴双下肢麻木及酸痛。查电解质大致正常，予止泻，患者腹泻缓解，但双下肢仍酸痛。2019年9月28日患者诉行走后头晕，测卧位血压130/80 mmHg，坐位血压106/67 mmHg，考虑体位性低血压，予补液。2019年9月29日患者出现发热（体温最高39.2 °C），无汗，无畏寒、寒战，未发现感染病灶，予积极抗感染及退热治疗后患者体温仍高（37.8～38.2 °C），查血常规：WBC 7.56×109/L，ANC 5.94×109/L，HGB 110 g/L，PLT 26×109/L；C反应蛋白、降钙素原、内毒素、GM试验、G试验和血培养均阴性。患者应用硼替佐米后出现典型的中枢性发热，伴明显的双下肢麻木疼痛及体位性低血压，不能排除硼替佐米的神经毒性，暂停化疗后患者接受中医治疗（针灸等）、营养神经等支持治疗，持续发热1周后开始出汗，体温逐渐降至正常，双下肢酸痛缓解，但仍有麻木。患者后续行Rd（来那度胺+地塞米松）方案巩固治疗，未再出现上述情况。
例5，男，67岁，2018年12月确诊为MM，后行BCD（硼替佐米+环磷酰胺+地塞米松）、VRD方案治疗，治疗期间患者反复出现低钠血症（血钠最低106 mmol/L）及一过性意识障碍，间断伴腹泻（大便次数最多达30次/d），生化常规示尿酸低（84 µmol/L）、尿素氮低（2.18 mmol/L），脑弥散加权成像（DWI）扫描未见异常扩散受限，不支持PRES。上述症状一般在应用硼替佐米2 d后出现，考虑硼替佐米不耐受，停用硼替佐米，后续应用Rd方案治疗，未再出现上述情况，疾病稳定。
上述5例患者的临床资料见表1。
表1 5例由硼替佐米引起中枢神经系统毒性的多发性骨髓瘤（MM）患者的临床资料
例号 性别 年龄（岁） 诊断 不良反应 症状 体温 PLT（×109/L） 血钠（mmol/L） 尿钠（mmol/L） 治疗方案 处理 转归
1 男 53 MM初治 SIAD；中枢性发热 表情淡漠、嗜睡、间断性意识障碍 持续发热、无汗 23 99.8 >40 VDD×2达PR→第3疗程VDD第2次硼替佐米注射 停用硼替佐米；限水、补钠、托伐普坦、氢化可的松减少尿钠；人血免疫球蛋白静滴减轻神经毒性；甘露醇减轻脑水肿 意识及行动逐渐恢复，血钠水平恢复正常。半年后患者出现疾病进展，使用Dara治疗无效，因疾病进展死亡
2 女 73 MM进展 中枢性发热；PRES；顽固性低钠血症 意识障碍 持续发热、无汗 15 122 24.73 BCD×4达CR→TD、MP方案治疗，持续CR→疾病进展→入组DVd临床试验，Vd第5个疗程第8天 停止化疗；托伐普坦、补钠；物理降温 后续未再化疗，未再出现低钠血症、持续性发热、意识障碍等情况，疾病稳定
3 男 62 MM进展 中枢性发热；顽固性低钠血症 精神萎靡 持续发热、无汗 17 127.2 NA BCD×3、VRD×3达PR→auto-HSCT后达VGPR→VRD×2巩固→Rd维持→疾病进展→Dara+VRD第1疗程 停用硼替佐米；冰袋物理降温；托伐普坦、补钠 改用Dara+IRD方案治疗；未再出现低钠血症、持续性发热
4 女 62 MM初治 中枢性发热 腹泻、体位性低血压、双下肢酸痛 持续发热、无汗 26 正常 NA VRD×5达sCR→第6疗程VRD第3次硼替佐米注射 停用硼替佐米；中医疗法（针灸） Rd方案治疗，未再出现持续性发热
5 男 67 MM初治 SIAD？ 精神淡漠，反应迟钝，腹泻 无 47 106 NA BCD×3、VRD 停用硼替佐米；限水、补钠 Rd方案治疗，未再出现低钠血症，疾病稳定
注：SIAD：抗利尿不当综合征；PRES：可逆性后部脑病综合征；sCR：严格意义的完全缓解；CR：完全缓解；VGPR：非常好的部分缓解；PR：部分缓解；VDD：硼替佐米+多柔比星脂质体+地塞米松；BCD：硼替佐米+环磷酰胺+地塞米松；TD：沙利度胺+地塞米松；MP：美法仑+泼尼松；DVd：达雷妥尤单抗（Dara）+硼替佐米+地塞米松；Vd：硼替佐米+地塞米松；VRD：硼替佐米+来那度胺+地塞米松；Rd：来那度胺+地塞米松；IRD：伊沙佐米+来那度胺+地塞米松；NA：未获得
讨论及文献复习
硼替佐米的CNS毒性很少报道，本文结合既往文献提出了硼替佐米CNS毒性的三种形式：SIAD、PRES和中枢性发热。
SIAD是指多种原因引起体内精氨酸加压素不恰当分泌、渗透压调定点“重置”或加压素受体突变造成的水潴留，以低渗性低钠血症、尿渗透压>血渗透压为特征的一组临床综合征[3]。SIAD一般与肿瘤、肺部疾病、CNS疾病以及药物有关[4]。患者出现高/正常血容量性低钠血症、低尿酸、低尿素氮和尿钠水平>40 mmol/L通常提示可诊断该综合征。
文献报道了7例考虑硼替佐米相关的SIAD（表2）[5]–[11]，男女比例相当。SIAD通常发生在硼替佐米治疗的第1～3疗程，停用硼替佐米、限制液体摄入、补高渗盐水等治疗后患者血钠及症状均可恢复。此外，精氨酸加压素拮抗剂托伐普坦在治疗硼替佐米导致的SIAD中也有重要价值[9],[11]。
表2 硼替佐米引起抗利尿不当综合征的文献报道
文献来源 性别 年龄（岁） 诊断 治疗方案 临床表现 血钠（mmol/L） 尿渗透压（mOsm/kg·H2O）（参考值：40～400） 尿钠（mmol/L）
Brodmann等[5] 女 77 MCL进展 第2疗程B单药 进行性共济失调、言语不清和意识混乱 112 317 94
Paydas等[6] 男 69 MM进展后缓解 第4疗程BD方案 嗜睡 123 升高 76
Shimazu等[7] 男 64 MM初治 第1～2疗程BD方案 嗜睡 110 525 145
Lv等[8] 男 44 MM初治 第3疗程BD方案 远端肢体疲乏及麻木 121.6 443 147.7
Carreño等[9] 女 81 MM初治 第2疗程BD方案 定向障碍、嗜睡和乏力 112 升高 NA
Peng等[10] 女 68 MM初治 第3疗程VMP方案 恶心呕吐、头晕、乏力 101 421 133
O'Connor-Byrne等[11] 女 67 MM二次进展 第1～2疗程BD方案 恶心、腹痛 118 503 70
文献来源 甲状腺功能 肾上腺皮质功能 ADH（pmol/L） 发热 PLT降低 CT/MRI 处理 转归
Brodmann等[5] NA NA NA 无 NA NA 限水补钠 停用硼替佐米，电解质恢复正常，评估疾病达完全缓解
Paydas等[6] 正常 正常 NA 无 有 NA 限水 停用硼替佐米，血钠恢复
Shimazu等[7] NA NA 2.4 有 有 正常 限水补钠 低钠血症纠正，但持续失眠，死于呼吸衰竭
Lv等[8] 正常 正常 NA 无 无 NA 限水补钠 血钠恢复，随后接受MPT方案治疗，血钠持续正常
Carreño等[9] 正常 正常 NA 无 NA 正常 限水托伐普坦 限水后一过性好转，2个月后症状再次出现，予托伐普坦后患者未再出现症状。疾病处于缓解状态
Peng等[10] 正常 正常 NA 有 NA NA 限水 改用MPR方案治疗，未再发生低钠血症，疾病控制良好
O'Connor-Byrne等[11] 正常 正常 NA 无 NA NA 限水补钠托伐普坦 血钠恢复正常，硼替佐米与托伐普坦同时应用后未再出现低钠血症
注：MCL：套细胞淋巴瘤；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；VMP：硼替佐米+美法仑+泼尼松；MPT：美法仑+泼尼松+沙利度胺；MPR：美法仑+泼尼松+来那度胺；ADH：抗利尿激素；NA：未获得
硼替佐米引起SIAD的机制尚不清楚，可能和长春新碱类似，通过对神经垂体和下丘脑系统的直接毒性导致渗透压调定点“重置”而引起SIAD[12]。此外，有研究通过免疫组织化学的方法发现单克隆浆细胞中抗利尿激素表达阳性，认为SIAD可能与肿瘤溶解综合征有关[13]，但这个机制不能解释获得疾病缓解的MM患者出现SIAD。
本研究5例患者中有4例发生了顽固性低钠血症，其中2例患者处于疾病缓解状态，3例既往应用硼替佐米时无不良反应。例1满足SIAD的诊断标准，排除了CNS疾病、肺部疾病及肿瘤溶解引起的SIAD，最终考虑与硼替佐米的CNS毒性有关。例5在硼替佐米治疗期间反复出现低钠血症，生化常规提示血浆渗透压低（低尿酸及低尿素氮），且在限水及补钠后血钠可恢复，停用硼替佐米后未再出现低钠血症，亦不能除外硼替佐米所致SIAD。
PRES是一种以头痛、癫痫发作、精神状态改变和视觉障碍为特征的临床综合征，产生机制是血管内皮功能障碍和脑自动调节功能失败，血脑屏障破坏，继而引起的脑水肿[14]，CT显示为等或低密度，MRI为T1W1等或低信号，T2W1高信号[14]–[15]。多数病例（70%～80%）与高血压相关，也可由子痫、肾功能不全、自身免疫性疾病和免疫抑制疗法（如环孢素和他克莫司）等引发[14],[16]，硼替佐米相关的PRES也陆续被报道[17]–[22]。
文献报道了6例硼替佐米相关PRES（表3），女性多见。PRES通常发生在硼替佐米应用的第1个疗程，也有报道发生在第2、3个疗程[17]–[18]，既往一线硼替佐米治疗耐受的患者挽救治疗时应用硼替佐米也可发生PRES[22]。硼替佐米相关PRES很大程度上可逆，停用硼替佐米、控制血压及癫痫后，2～3 d内神经症状可缓解，数周后复查影像学可见病灶消失[19]。
表3 硼替佐米引起可逆性后部脑病综合征（PRES）的文献报道
文献来源 性别 年龄（岁） 诊断 血压（mmHg） 临床表现 CT/MRI 脑脊液
Kelly等[17] 男 66 WM难治 中度高血压 全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：枕叶的皮质下白质中显示出广泛的不对称高信号 NA
Kager等[18] 女 62 MM进展 183/94 视物模糊、头痛、癫痫、精神状态改变（嗜睡） 脑CT：皮层下和顶枕白质中存在低密度区域 NA
Terwiel等[19] 女 58 MM进展 升高 无痛性双侧视力下降、强直-阵挛性癫痫发作 脑MRI：双侧枕部皮质及白质不对称高信号 NA
Oshikawa等[20] 女 54 MM初治 140/85 全身性强直-阵挛性癫痫发作、精神状态改变（嗜睡） 脑MRI：枕叶和丘脑皮层下白质中广泛不对称高强度信号 蛋白细胞分离（细胞数：3/mm3，总蛋白：95 mg/dl）；HSV、VZV和HHV-6分子检查均为阴性
Ho等[21] 女 51 MM初治 217～184/ 125～98 视物模糊、头痛、全身性强直-阵挛性癫痫发作、精神状态改变 脑MRI：双侧额顶叶至枕叶皮质下区高信号 NA
Nixon等[22] 女 71 MM进展 175/67 额叶搏动性头痛、全身性强直-阵挛性癫痫发作 脑CT：枕叶白质可见低密度区。脑MRI：大脑白质双侧弥漫性水肿，主要累及脑桥和小脑 NA
文献来源 治疗方案 处理 转归
Kelly等[17] 第3疗程B单药 停用硼替佐米；予降压药 未再发作，3个月后复查脑MRI正常
Kager等[18] 第2疗程BD方案 停用硼替佐米；拉贝洛尔降压治疗；劳拉西泮治疗癫痫 约3 d神经症状消失
Terwiel等[19] 第1疗程BD方案 停用硼替佐米；拉贝洛尔和氨氯地平降压；苯妥英钠治疗癫痫发作 视力在数周内逐渐恢复，但没有完全恢复。2周后复查MRI脑水肿消失。数月后死于MM进展
Oshikawa等[20] 第1疗程BD方案 停用硼替佐米；甲泼尼龙冲击治疗：1 g/d，连续3 d 意识两天内恢复正常，未再有癫痫发作。1周后和1个月后复查脑MRI显示大脑病变有显著改善
Ho等[21] 第1疗程BT方案 地西泮、丙戊酸控制抽搐；尼卡地平控制血压 2 d后症状恢复，2周后复查脑MRI显示疾病明显缓解
Nixon等[22] 一线治疗曾应用VMP方案达部分缓解，疾病进展后挽救治疗第1疗程VMP方案时出现PRES 苯妥英钠；插管以保护气道；静脉注射拉贝洛尔降血压 神经症状未再发作，5个月后死于难治性MM
注：WM：华氏巨球蛋白血症；MM：多发性骨髓瘤；B：硼替佐米；BD：硼替佐米+地塞米松；BT：硼替佐米+沙利度胺；VMP：硼替佐米+美法仑+泼尼松；HSV：单纯疱疹病毒；VZV：水痘-带状疱疹病毒；HHV-6：人疱疹病毒-6型；NA：未获得
硼替佐米导致PRES的机制尚不明确，可能机制如下：①硼替佐米抑制NF-κB的激活，导致包括血管内皮生长因子（VEGF）在内的细胞生长因子转录水平降低。此前研究表明，抗VEGF的药物如贝伐单抗可通过影响内皮细胞功能破坏血脑屏障进而引起PRES[23]。因此，硼替佐米可能通过NF-κB途径对血脑屏障产生破坏，导致PRES。②硼替佐米还可能通过引起自主神经功能障碍导致脑血管收缩、痉挛，进而产生PRES。
例2考虑存在PRES，患者在应用硼替佐米后出现一过性精神状态改变（意识障碍），且头CT示双侧半卵圆中心白质密度减低，患者虽有低钠血症，但其血钠水平（122～130 mmol/L）一般很少导致意识障碍，在停用硼替佐米及普通支持治疗后其精神症状可逆，结合患者发病特点及影像学检查，诊断其合并PRES。既往文献报道，有37% CT阴性的患者MRI诊断为PRES[24]，因而若怀疑患者存在PRES，推荐首选头MRI检查作为PRES诊断的“金标准”。
除顽固性低钠血症及精神状态改变外，本文报道的5例患者中有4例在应用硼替佐米治疗后的2～5 d内出现了持续性高热，其共同特点为：①持续数日至数周的高热；②周身无汗；③虽然高热，但中毒症状不明显，未发现感染灶且抗感染治疗无效；④予退热药后体温仍高，物理降温有效。综合上述特点考虑患者为中枢性发热，而停用硼替佐米后未再出现，我们认为硼替佐米与其高度相关。众所周知，人体的体温调节中枢位于下丘脑，下丘脑前部病变，特别是视前区体温敏感神经元的病变，会引起体温整合功能障碍，从而导致中枢性高热[25]。本文报道的4例患者中有3例同时合并顽固性低钠血症，且1例明确诊断为SIAD，抗利尿激素的合成也位于下丘脑，因此我们推测，硼替佐米可能通过影响下丘脑导致中枢性发热和SIAD同时发生。
此外，5例患者在硼替佐米CNS不良反应发生期间均有3～4级血小板减少，且血小板减少的严重程度和临床症状（如发热、低钠血症、精神状态等）的严重程度一致（图1、2）。既往文献报道，脑源性神经营养因子（BDNF）主要在人血小板中储存和运输，对神经纤维和神经元起营养支持作用[26]，BDNF的减少和硼替佐米诱导的周围神经病变有关[27]。因而，我们推测硼替佐米诱发CNS毒性的另外一个可能的机制为硼替佐米引起PLT降低，使得BDNF释放减少，进而间接损伤CNS。PLT或许可作为硼替佐米CNS毒性严重程度的预判指标。
图1 例1治疗过程中PLT（A）及体温、血钠（B）变化
图2 例4治疗过程中体温及PLT变化
硼替佐米的CNS毒性为相对少见的不良反应，我们在此报道并进行文献复习，希望提高广大医师对该不良反应的认识。 | Recovered | ReactionOutcome | CC BY-NC-SA | 33677871 | 19,207,262 | 2021-01-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | INFLIXIMAB, MERCAPTOPURINE | DrugsGivenReaction | CC BY-NC-ND | 33678739 | 19,105,218 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | ACETAMINOPHEN, CLOSTRIDIUM BUTYRICUM SPORES STRAIN M-55, FEXOFENADINE HYDROCHLORIDE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE | DrugsGivenReaction | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What is the weight of the patient? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | 49 kg. | Weight | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What was the administration route of drug 'ACETAMINOPHEN'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What was the administration route of drug 'CLOSTRIDIUM BUTYRICUM SPORES STRAIN M-55'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What was the administration route of drug 'FEXOFENADINE HYDROCHLORIDE'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What was the administration route of drug 'INFLIXIMAB'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What was the administration route of drug 'MERCAPTOPURINE'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What was the administration route of drug 'MESALAMINE'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
What was the dosage of drug 'MERCAPTOPURINE'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | 30 MG | DrugDosageText | CC BY-NC-ND | 33678739 | 19,105,218 | 2021-08-15 |
What was the outcome of reaction 'Cerebral venous sinus thrombosis'? | High-dose-infliximab-associated Cerebral Venous Sinus Thrombosis: A Case Report and Review of the Literature.
A 28-year-old woman experienced severe headache and right homonymous hemianopia after receiving high-dose infliximab for Crohn's disease. Computed tomography showed hemorrhagic infarction in the left temporal and parietal lobes. An angiogram revealed left transverse to sigmoid sinus occlusion and a stagnated Labbe vein. The patient was treated surgically and achieved a good outcome. Inflammatory bowel diseases are known to accompany venous and arterial thrombosis in 1-2% of cases. Recently, infliximab has been suggested to increase this possibility. A case of Crohn's disease presenting with cerebral sinus thrombosis in the remission period during long-term/high-dose use of infliximab is presented. In addition, infliximab-associated thrombosis cases were reviewed.
pmcIntroduction
Inflammatory bowel disease (IBD) refers mainly to ulcerative colitis (UC) and Crohn's disease (CD). Often affecting women in their 20s and 30s, its prevalence is increasing year by year. Thrombosis is a major adverse event in patients with IBD because of its severe symptoms (1,2).
In a cohort study of 13,756 IBD patients, IBD revealed an overall hazard ratio of 3.4 in venous thromboembolism patients compared to controls (3). This ratio was high in the flare [8.4] and chronic activity phase [6.5] but low in the remission period [2.1]. It was also reported to be more likely to occur in UC than in CD patients (4). Cerebral infarction is also known to give rise to complications in IBD patients (5). A literature review in 2014 by Katsanos et al. reported cases with arterial cerebral thromboembolic complications among 33 IBD patients (6). Concerning cerebral venous thrombosis in IBD patient, it has also been found that seven out of nine cases of cerebral infarction were due to sinus thrombosis in one series (8).
Infliximab (IFX) is a potent anti-tumor necrosis factor (TNF) antibody, highly effective in IBD patients (8,9). It is also widely used to treat chronic inflammatory diseases, such as rheumatoid arthritis, Behcet's disease, ankylosing spondylitis, psoriasis vulgaris, and Kawasaki disease, in their acute phases (10-14). IFX is effective even in steroid-resistant IBD patients (15). Infection (16,17) and the development of malignancy, especially systemic lymphoma (18), are well-known adverse events of IFX. Furthermore, it seems likely that the administration of IFX to IBD patients further increases the risk of venous or arterial thrombotic complications. At present, nine cases of thromboembolic complications have been reported in patients with IBD treated using IFX (Table). Puli et al. reported the first case in 2003, wherein retinal vein thrombosis occurred after the third administration of IFX in a CD patient (19). The location and timing of the thromboembolic complications have been widely inconsistent among these patients.
Table. Thromboembolic Complications in Patients with IBD after IFX Administration.
No. Age
(y) Sex Disease Stage of
IBD IFX
dosage
(mg/kg) Cycle of IFX Onset after
IFX
administration Location of thrombosis Reference
1 45 F CD flare 5 3 UNK Retinal vein thrombosis 19
2 73 M UC UNK UNK 1 2 weeks Pulmonary embolism 23
3 31 F CD active 5 3 30 minutes Forearm vein thrombosis 21
4 40 M CD active 5 3 3 days Acute coronary syndrome 25
5 67 M UC remission 5 6 2 weeks Retinal vein thrombosis 20
6 33 F UC remission UNK 3 4 weeks Inferior vena cava and
renal vein thrombosis 24
7 48 M CD active 5 2 3 days Femoral artery occlusion 26
8 44 M UC flare 5 1 3 days Acute renal artery occlusion 27
9 27 F CD active 5 2 5 hours Radial cutaneous vein thrombosis 22
10 28 F CD remission 10 11 (5 mg/kg)
22 (10 mg/kg) 5 days Cerebral sinus thrombosis Current case
CD: Crohn's disease, F: female, IBD: inflammatory bowel disease, IFX: infliximab, M: male, UC: ulcerative colitis, UNK: unknown
To our knowledge, this is the first case report of cerebral venous sinus thrombosis after high-dose IFX administration in an endoscopic remission phase. In addition, we summarize cases of thromboembolic complication occurring after IFX administration in IBD in an attempt to characterize the thromboembolic complications. The present case report highlights the importance of a sinus thrombosis diagnosis in patients undergoing long-term high-dose IFX therapy and assesses the optimal treatment options for achieving a favorable outcome in such patients.
Case Report
A 28-year-old woman was sent to our center because of severe headache and right homonymous hemianopia. She had been diagnosed with CD at another hospital five years earlier and was receiving treatment there. Initially, her disease had been controlled using mesalazine but later had required the additional use of oral steroid due to deterioration. Despite four weeks of high-dose steroid administration, her CD remained active and refractory to conventional medical therapy. Therefore, steroids were discontinued, and IFX was started.
IFX had been introduced at a regular dose (5 mg/kg) with an 8-week interval starting 4 years earlier. Despite 11 cycles of IFX (5 mg/kg), her CD remained active indicating that she was refractory to conventional medical therapy. The patient was therefore treated using high-dose IFX at 10 mg/kg followed by a total of 22 cycles with a 6-week interval. She had recently maintained disease remission with mercaptopurine hydrate 30 mg and high-dose IFX.
At 5 days after the last high-dose IFX administration, she experienced rapidly worsening headache and visual disturbance. Her blood examination results were as follows: white blood cell count, 5,800/mL; hemoglobin, 9.5 g/dL; and platelet count, 222,000/mL. Major blood biochemistry data were within normal values. The coagulation/fibrinolysis parameters were as follows: activated partial thromboplastin time (APTT), 26.4 seconds (normal 27 to 45), prothrombin time (PT), 13.8 seconds (normal 10 to 13); international normalized ratio (INR), 1.16; fibrinogen, 299 mg/dL (normal 150 to 400); D-dimer, 3.0 μg/mL (normal <1.0); thrombin-antithrombin (TAT) complex, 5.8 ng/mL (normal <3.0); homocysteine, 13.4 nmol/mL (normal 3.7 to 13.5); protein C activity, 83% (normal 64% to 146%); and protein S activity, 54% (normal 56% to 126%). The factors involved in the congealing fibrinogenolysis system (D-dimer, TAT complex) were slightly elevated temporarily. Anti-nuclear antibody was strongly positive (1:640 dilutions, above 1:160 as positive), anti-cardiolipin antibody was within the normal range (8 U/mL, normal <10), and the anti-double stranded DNA antibody level was 12 IU/mL, which was at the upper limit of normal. The erythrocyte sedimentation rate was elevated at 47 mm/h (normal <15). An IFX screening test was positive. Vasculitis and sepsis screening results were normal.
Brain computed tomography revealed hemorrhagic infarction in the left parietal and temporal lobes. Magnetic resonance imaging (MRI) and three-dimensional computed angiography demonstrated left transverse to sigmoid sinus thrombosis and Labbe vein congestion (Fig. 1). Cerebral angiography revealed a left transverse to sigmoid sinus thrombus extending into the Labbe vein. In addition, a distant thrombus was found in the anterior segment of the superior sagittal sinus. Her consciousness level gradually worsened along with increasing intracranial pressure. MRI before emergency surgery (Fig. 2A-D) revealed vasogenic edema in the left temporal lobe with a high signal intensity on apparent diffusion coefficient map.
Figure 1. Brain magnetic resonance imaging T1 image on admission. A high-intensity signal is observed in the transverse to sigmoid sinus (left panel) and Labbe vein (central panel) suggesting the presence of thrombosis (arrow). 3D computed angiography shows sinus occlusion (arrowheads) in the transverse to sigmoid sinus (right panel).
Figure 2. Brain magnetic resonance imaging on admission (A: DWI, B: ADC map, C: FLAIR, D: T2*). Brain magnetic resonance imaging at one month after onset (E: DWI, F: ADC map, G: FLAIR, H: T2*). The high-intensity signal (arrowheads) was reduced, and no new lesions were observed.
She underwent emergency external decompression surgery to decrease the intracranial pressure. After surgery, her consciousness completely recovered, and treatment was continued with low-molecular-weight heparin (LMWH) and osmotic diuretics. The patient was treated with anticoagulation measures comprising LMWH 75 IU/kg/day for 10 days. Anticoagulation was initiated with warfarin 2-3 mg orally once daily after bridging with LMWH. The dose was adjusted to maintain the patient's INR at 2 to 3. She had only maintained disease remission with a mesalazine 3,000 mg and mercaptopurine hydrate 30 mg during treatment of cerebral venous thrombosis. At one month after surgery, remarkable improvement in the MRI findings was observed (Fig. 2E-H). She returned to her own life without any neurological deficit after undergoing cranioplasty surgery.
A blood examination was repeated at six months after surgery. The coagulation/fibrinolysis parameters were as follows: APTT, 29.2 seconds, PT, 16.4 seconds; INR, 1.28; fibrinogen, 218 mg/dL; D-dimer, 1.0 μg/mL; TAT complex, 1.0 ng/mL; protein C activity, 124%; and protein S activity, 96%. Anti-nuclear antibody became negative (1:80 dilutions), and the double stranded DNA antibody level was 2.9 IU/mL (normal <12) in the interval periods of IFX treatment. The erythrocyte sedimentation rate was normalized at 7 mm/h. Anti-coagulation therapy was discontinued at six months after surgery because of a negative test for anti-nuclear antibodies. No further treatment was required, except for a reduction in the IFX dosage. Follow-up brain MRI demonstrated a small old infarction in the left inferior temporal gyrus at 10 months after the onset.
Discussion
To our knowledge, there have been nine cases of venous thrombosis/arterial occlusion associated with IFX administration. Among these patients, two developed retinal vein thrombosis (19,20), two developed forearm vein thrombosis (21,22), one developed pulmonary embolism (23), one developed inferior vena cava thrombosis (24), and three developed artery occlusion (25-27). Panteris et al. noted that thrombosis is frequently observed at three to seven days after IFX administration (25). Ljung et al. emphasized that the use of IFX in IBD patients increases the possibility of adverse events and mortality (23). Among 217 patients who received IFX in that study, 6 fatal adverse events were found, including 2 cases with lymphoma, 3 cases with severe infection (sepsis), and 1 with pulmonary embolism. Several adverse events related or unrelated to embolism may occur following IFX administration (28,29).
The relative risk of a thromboembolic event increases above 3-fold in IBD patients and exceeds 16-fold during non-hospitalized flare phase periods (3). Cerebral venous thrombosis is rarely associated with IBD. An estimated 1.3-6.4% of patients with IBD experience cerebral venous thrombosis at some point during the course of the disease (30). Cerebral venous thrombosis is more common in UC than in CD (4); indeed, cerebral venous thrombosis has only rarely been reported in patients with CD. What makes patients with IBD susceptible to venous thrombosis has been investigated but is still poorly understood, but there has been some speculation. Immobilization, surgery, intra-venous catheters, using steroid, and coagulation/fibrinolysis disorders may be a cause in some patients. However, the present patient had not been exposed to such additional risks or underlying coagulation/fibrinolysis disorders. Systemic factors appear to be the major reason that activated coagulation/fibrinolysis cascade occurred in the present case.
The expression of TNF-α receptors has been proposed as a possible reason for thrombosis occurring in IBD patients after IFX administration (25). The TNF-α driven procoagulant loop increases the incidence of thrombosis after TNF-α administration, and conversely, TNF-α inhibition reduces the incidence of venous thrombosis (31). A counter-regulation mechanism might upregulate the expression of TNF-α receptors on the inflammatory cell membrane when IFX administration leads to a reduction in serum TNF-α levels, resulting in thrombus formation (25). This so-called “paradoxical thrombus formation” is one reason for thrombosis being caused by IFX administration. In addition, it was suggested that IFX can also lead paradoxical thrombus formation if administered at a dose of 10 mg/kg.
Molecular-targeted drugs may induce various autoantibodies, including anti-nuclear, anti-double stranded DNA, anti-cardiolipin and anti-phospholipid antibodies. Autoantibodies are the most prominent factor in thrombophilia and may contribute to the development of systemic lupus erythematosus-like syndrome (drug-induced lupus erythematosus) secondary to molecular-targeted drug administration. In addition, some authors have suggested that the emergence of autoantibodies after IFX administration may be related to a transient increase in TNF-α (32). The sinus thrombosis in our case appears to have resulted from temporarily elevated autoantibodies and coagulation/fibrinolysis disorder, since these factors became normalized after the dose of IFX was reduced. The expression of autoantibodies seems to be another reason for “paradoxical thrombus formation.”
Infusion reactions (IRs) are another possible mechanism responsible for thrombosis. Molecular-targeted drugs are known to increase the risk of thrombosis by causing severe IRs. Ryan et al. indicated that IFX can cause thrombus formation via IRs (21). In their report, IRs developed in 10-20% of cases after IFX administration (17,33), commonly occurring at a mild to moderate level, although approximately 2% presented with severe IRs. Repeated use of IFX is a risk factor for severe IRs. Severe IRs are characterized by anaphylactoid symptoms that occur within 24 hours of administration (17). The mechanism underlying IFX-induced IRs has not yet been elucidated but is considered to be related to the temporary release of cytokines. Cytokine release can lead to the activation of the platelet agglutinin ability and thrombus formation, similar to disseminated intravascular coagulation (DIC) syndrome (21,22).
In the present case, sinus thrombosis occurred during the remission phase, shortly after high-dose IFX administration. Since autoantibodies had already formed when the sinus thrombosis became symptomatic and cerebral angiography demonstrated thrombosis in the superior sagittal sinus, it seems likely that asymptomatic thrombosis was occurring repeatedly before becoming symptomatic in this case. Care must be taken to administer IFX therapy at an appropriate dosage and interval in order to prevent thromboembolic complications. On this point, blood examinations including autoantibody measurements might be useful for indicating the presence of asymptomatic thrombosis. In addition, the timing of thromboembolic complications varied from the first administration to 33rd cycle in our case. Furthermore, the time lag between the thrombosis onset and the final IFX administration varied from 30 minutes to 4 weeks. It is worth noting that thromboembolic complications might occur with any timing, probably because several mechanisms exist for thrombus formation.
The present case demonstrated full clinical recovery after treatment with external decompression and low-molecular-weight heparin. No further treatment was required, except for a reduction in the IFX dosage. The prognosis of sinus thrombosis is usually favorable, with more than 80% of patients achieving a good clinical outcome (34). In fact, follow-up brain MRI and magnetic resonance venography did not reveal the recurrence of venous thrombosis in our case. Nevertheless, because long-term use of IFX is necessary in some IBD cases, strict observation is needed to detect variable complications.
In conclusion, there is a possible risk of cerebral sinus thrombosis with IFX treatment. This case report highlights the need to clarify the details and incidence of adverse events occurring during long-term/high-dose use of IFX.
The authors state that they have no Conflict of Interest (COI). | Recovered with sequelae (consequent health issues) | ReactionOutcome | CC BY-NC-ND | 33678739 | 14,020,335 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Ramucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases.
Pyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.
pmcIntroduction
Pyogenic granuloma (PG) is a granulomatous, elevated lesion that occurs on the skin and mucous membranes (1). Clinically, this lesion grows without pain, and frequently appears as a hemorrhagic, red-purple, venous or perforating tumor mass (2). It may grow rapidly, and needs to be differentiated from malignant tumors. PGs are commonly found in the face and limbs. In the oral region, the gingiva, lip, and tongue are common sites (1,3).
PG arises from various stimuli, including chronic low-grade irritation, traumatic injury, hormones, and drugs (1). The pathogenesis of pyogenic granuloma at the molecular level is unclear, but may be considered as resulting from the imbalance of angiogenesis enhancers and inhibitors (4).
It has been reported that PG and angioma can develop during the administration of ramucirumab, an angiogenesis inhibitor (5-7). Most of these reports describe skin lesions, and to our knowledge, no detailed studies have been published on oral lesions, especially from the point of view of histopathology. Therefore, in this study, we report two cases of PG that occurred in the oral cavity during the administration of ramucirumab. The study protocol adhered to the recommendations in the Declaration of Helsinki and the study was approved by the regional Ethical Review Board of our Institution.
Case Report
Case 1
A 55-year-old man presented to our department with swelling of the right tongue. He was diagnosed with stage IV (T4aN2M1) gastric cardia cancer. Combination chemotherapy with capecitabine+cisplatinum+trastuzumab therapy was started; owing to tumor growth, however, chemotherapy was stopped after eight courses, and new combination chemotherapy with ramucirumab+weekly paclitaxel was initiated. In each four-week course, ramucirumab was administered once every two weeks with paclitaxel for three consecutive weeks, with a one-week break. After four courses of treatment, computed tomography (CT) showed that the tumor had shrunk by more than 30%; this indicated a partial response (PR) to treatment according to the Response Evaluation Criteria in Solid Tumors.
After seven courses, a tumor was found on the right tongue. An initial physical examination revealed a 6-mm extroverted, elastic, soft mass (Fig. 1a). The mass was painless and involved the upper and lower canines and premolars. Hemorrhaging was also observed from the gingiva of the lower anterior region, and the crown of the right upper second molar was missing. On panoramic imaging, the upper right maxillary second molar had a residual root (Fig. 1b). The patient had no family dentist and had not received dental care for more than three years. Daily prevention at home was performed only once a day.
Figure 1. Clinical and imaging characteristics of case 1. (a) Macroscopic findings. A pedunculated tumor of approximately 6 mm can be seen on the right side of the tongue. Slight bleeding is seen from the left lower anterior gingiva. (b) Panoramic image: Moderate marginal alveolar bone resorption is seen. The upper right maxillary second molar had a residual root (*).
The tumor showed rapid growth and was therefore resected under local anesthesia; no abnormal bleeding was observed. Histopathological findings of oral specimens obtained from the tongue tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 2a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 2b). For immunostaining, heat-induced antigen retrieval was performed by incubating the sections with 10 mM Tris base containing 1 mM ethylenediaminetetraacetic acid (pH 9.0). In order to detect vascular endothelial growth factor receptor-2 (VEGFR2), CD31, D2-40, and Ki-67, a section was incubated with anti-VEGFR2 rabbit monoclonal antibody (clone 55B11; Cell Signaling Technology, Danvers, USA), anti-CD31 (clone 1aA10; Novocastra Laboratories, Newcastle upon Tyne, UK), anti D2-40 (clone D2-40; Nichirei Bioscience, Tokyo, Japan), and Ki-67 (MIB-1; Dako, Glostrup, Denmark), followed by incubation with an anti-rabbit peroxidase polymer (Nichirei Bioscience). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 2c-f). After treatment at our department, ramucirumab was discontinued due to cancer progression on CT. The patient subsequently received other drugs but died six months after visiting our department; the oral lesions did not recur after the discontinuation of ramucirumab.
Figure 2. Histopathological characteristics of case 1. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) Endothelial cells positive for CD31 (c) and negative for D2-40 (d) can be seen. (e) Strong immunostaining for vascular endothelial growth factor receptor-2 (VEGFR2) can be seen in almost all vascular endothelial cells. (f) Cell proliferation marker Ki-67 is also frequently detected.
Case 2
A 67-year-old man was admitted to our department owing to a tumor on the upper lip. He had been diagnosed with stage IIIB (cT3N3aM0) gastric cancer six years previously, and distal gastrectomy had been performed at the gastrointestinal surgery department of our hospital; S-1 was administered for 1 year as postoperative adjuvant chemotherapy. Four years later, magnetic resonance imaging showed cancerous peritonitis; S-1 was therefore restarted. Owing to the evidence of lesions on a CT examination three months later, XELOX therapy was started. Since disease progression was observed after 22 courses, combination chemotherapy was started with ramucirumab+nab-paclitaxel. In each four-week course, ramucirumab was administered once every two weeks along with nab-paclitaxel for three consecutive weeks and a one-week break. At the end of six courses, CT showed no obvious change in the tumor size and increased ascites; this indicated stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors.
During the fifth course, a tumor appeared on the upper lip. The lip tumor fell off spontaneously but subsequently recurred and increased in size; the patient was therefore referred to our department during the seventh course. On an initial physical examination, a 5-mm elastic soft mass was observed on the right upper lip. In addition, the crown of the upper left central incisor was fractured (Fig. 3a). Oral care was found to be poor, and the periodontal pocket was deep overall, reaching 6 mm at the right maxillary canine. The left maxillary central incisor and lateral incisors showed moderate instability; the mandibular partial denture was not sufficiently stable. Panoramic imaging showed multiple residual roots, with a fracture at the upper right first molar (Fig. 3b). The patient's family had a dental clinic, but he had not undergone intensive treatment after the initiation of anticancer drug therapy. A benign tumor was diagnosed at the upper lip and was excised under local anesthesia; the fractured piece of the upper left central incisor was also removed simultaneously. No abnormal bleeding was observed from the sutures nine days later.
Figure 3. Clinical and imaging characteristics of case 2. (a) Macroscopic findings: a 5-mm extroverted, elastic, soft mass can be seen on the upper right lip. (b) Panoramic image: Moderate to high marginal alveolar bone resorption can be seen. A horizontal root fracture can be seen in the upper first molar (*); both maxillary sinuses are deformed.
The histopathological findings of the oral specimens obtained from the lip tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 4a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 4b). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 4c-f).
Figure 4. Histopathological characteristics of case 2. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) CD31 (c) and D2-40 (d) immunostaining: endothelial cells are positive for CD31 and negative for D2-40. (e) Vascular endothelial growth factor receptor-2 (VEGFR2) immunostaining. Strong staining can be seen in almost all vascular endothelial cells. (f) The Ki-67 cell proliferation marker is also frequently detected in vascular endothelial cells.
After starting treatment, the patient presented with a generalized pruritic skin rash; difluprednate ointment was prescribed. At the same time as the visit to our department, pruritus was observed on the back; a 1-cm tumor also appeared, which required resection at a nearby dermatology clinic. A histopathological examination showed capillary lobular growth with vascular endothelial cell proliferation, suggestive of a pyogenic granuloma. Since exacerbation of the cancerous peritonitis was confirmed on CT after 12 courses, ramucirumab+paclitaxel therapy was discontinued at 6 months after the initial visit to our department, and nivolumab therapy was started. After resection, there was no evidence of recurrence of the oral or skin tumors.
Discussion
To our knowledge, this is the first report concerning the histopathological examination of oral PG in patients receiving ramucirumab. The causes of PG were considered to be the systemic deterioration of the angiogenic balance by ramucirumab and the locally deteriorated oral environment (4). Angiogenesis is an important characteristic of cancer; malignant tumors create new vascular networks to meet their increased demand for oxygen and nutrients and to achieve efficient removal of metabolic waste. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been identified as major regulators of angiogenesis (8,9). VEGFR2 is a major mediator of VEGF-induced angiogenesis and exhibits the most potent tyrosine kinase activity; it is being investigated as a target of anti-angiogenic therapy for cancer (10).
Ramucirumab is a fully human IgG1 monoclonal antibody that selectively binds to the extracellular domain of VEGFR2 (9,11). It is mainly used as a second-line treatment for advanced cancers, such as gastric, colorectal, and non-small-cell lung cancers (11). The Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma trial, which was the first randomized phase III study on advanced gastric cancer, revealed that ramucirumab therapy was beneficial in terms of the overall survival compared with placebo in a second-line treatment setting (8,12). The combination of ramucirumab with paclitaxel significantly increases the overall survival compared with placebo plus paclitaxel in advanced gastric or gastro-esophageal junction adenocarcinoma patients (11,12). Various adverse events have been reported in relation to ramucirumab, including hypertension, deep vein thrombosis, headaches, anorexia, vomiting, and dyspnea (8,11). Interestingly, there are several reports on PGs and hemangiomas occurring in patients receiving ramucirumab. Lim et al. first reported the development of an angioma during the administration of ramucirumab in 2015 (5); several cases have been reported since then, including sporadic and multiple occurrences (5-7); tumors appeared at a minimum of two months and a maximum of six months after starting ramucirumab (5-7). The pathogenesis of ramucirumab-related PG remains unknown. Ibe et al. reported on a case of PG of the fingers, where strongly positive immunostaining was observed for VEGFR2; they hypothesized that following ramucirumab administration, a small wound triggered VEGFR2 overexpression owing to a mutation in KDR (p.T771R), which is a driver of vascular lesions (6).
PG in our two cases developed during the administration of ramucirumab. The tumor appeared during the fourth and sixth course in cases 1 and 2, respectively. From the clinical course, ramucirumab appeared to be involved in the formation of PG. The first case in the oral cavity was sporadic. However, in the second case, PG also developed in the skin of the back; it was therefore considered to be a case of multiple PG. On immunostaining, both cases tested positive for VEGFR2 and CD31, which are expressed in blood vessels; they tested negative for D2-40, which is expressed in lymphatic vessels. The expression of the growth factor Ki-67 was also observed. These results showed that the overexpression of VEGFR2 caused the excessive proliferation of small blood vessels, leading to PG.
The findings from these cases suggest that the oral environment was also involved in PG formation. The oral cavity is easily damaged by caries, periodontal disease, defective teeth or bite, food, and poor oral cleaning. In these two cases, the oral environment was poor, and dental care was insufficient. In addition to the administration of ramucirumab, intraoral stimulation by the residual roots and sharp edges of the dentures were also suspected of having induced the development of PGs.
A limitation of this study is that the frequency of ramucirumab-related PG and the difference in characteristics from other PGs were not determined. Further large-scale studies are needed to elucidate the characteristics and etiology of oral PG in patients treated with ramucirumab. Among the oral adverse events caused by specific drugs used in anticancer treatment, everolimus-related stomatitis and medication-related osteonecrosis of the jaw due to bone resorption inhibitors, such as bisphosphonates and denosumab, are well known. The frequency of ramucirumab-related PG is unknown, but the use of ramucirumab is increasing; the incidence of oral PG is therefore expected to increase in the future. Medical and dental interprofessional collaboration is essential for investigating the possibility of oral PG development during the administration of ramucirumab.
In conclusion, we encountered two cases of ramucirumab-related oral PG. The deterioration in the local angiogenic balance caused by ramucirumab and the poor oral environment contributed to the formation of PG. Oncologists and dentists should carefully consider the development of oral symptoms and their management.
The authors state that they have no Conflict of Interest (COI). | CAPECITABINE, CISPLATIN, PACLITAXEL, RAMUCIRUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33678742 | 19,848,131 | 2021-08-15 |
What was the dosage of drug 'CAPECITABINE'? | Ramucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases.
Pyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.
pmcIntroduction
Pyogenic granuloma (PG) is a granulomatous, elevated lesion that occurs on the skin and mucous membranes (1). Clinically, this lesion grows without pain, and frequently appears as a hemorrhagic, red-purple, venous or perforating tumor mass (2). It may grow rapidly, and needs to be differentiated from malignant tumors. PGs are commonly found in the face and limbs. In the oral region, the gingiva, lip, and tongue are common sites (1,3).
PG arises from various stimuli, including chronic low-grade irritation, traumatic injury, hormones, and drugs (1). The pathogenesis of pyogenic granuloma at the molecular level is unclear, but may be considered as resulting from the imbalance of angiogenesis enhancers and inhibitors (4).
It has been reported that PG and angioma can develop during the administration of ramucirumab, an angiogenesis inhibitor (5-7). Most of these reports describe skin lesions, and to our knowledge, no detailed studies have been published on oral lesions, especially from the point of view of histopathology. Therefore, in this study, we report two cases of PG that occurred in the oral cavity during the administration of ramucirumab. The study protocol adhered to the recommendations in the Declaration of Helsinki and the study was approved by the regional Ethical Review Board of our Institution.
Case Report
Case 1
A 55-year-old man presented to our department with swelling of the right tongue. He was diagnosed with stage IV (T4aN2M1) gastric cardia cancer. Combination chemotherapy with capecitabine+cisplatinum+trastuzumab therapy was started; owing to tumor growth, however, chemotherapy was stopped after eight courses, and new combination chemotherapy with ramucirumab+weekly paclitaxel was initiated. In each four-week course, ramucirumab was administered once every two weeks with paclitaxel for three consecutive weeks, with a one-week break. After four courses of treatment, computed tomography (CT) showed that the tumor had shrunk by more than 30%; this indicated a partial response (PR) to treatment according to the Response Evaluation Criteria in Solid Tumors.
After seven courses, a tumor was found on the right tongue. An initial physical examination revealed a 6-mm extroverted, elastic, soft mass (Fig. 1a). The mass was painless and involved the upper and lower canines and premolars. Hemorrhaging was also observed from the gingiva of the lower anterior region, and the crown of the right upper second molar was missing. On panoramic imaging, the upper right maxillary second molar had a residual root (Fig. 1b). The patient had no family dentist and had not received dental care for more than three years. Daily prevention at home was performed only once a day.
Figure 1. Clinical and imaging characteristics of case 1. (a) Macroscopic findings. A pedunculated tumor of approximately 6 mm can be seen on the right side of the tongue. Slight bleeding is seen from the left lower anterior gingiva. (b) Panoramic image: Moderate marginal alveolar bone resorption is seen. The upper right maxillary second molar had a residual root (*).
The tumor showed rapid growth and was therefore resected under local anesthesia; no abnormal bleeding was observed. Histopathological findings of oral specimens obtained from the tongue tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 2a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 2b). For immunostaining, heat-induced antigen retrieval was performed by incubating the sections with 10 mM Tris base containing 1 mM ethylenediaminetetraacetic acid (pH 9.0). In order to detect vascular endothelial growth factor receptor-2 (VEGFR2), CD31, D2-40, and Ki-67, a section was incubated with anti-VEGFR2 rabbit monoclonal antibody (clone 55B11; Cell Signaling Technology, Danvers, USA), anti-CD31 (clone 1aA10; Novocastra Laboratories, Newcastle upon Tyne, UK), anti D2-40 (clone D2-40; Nichirei Bioscience, Tokyo, Japan), and Ki-67 (MIB-1; Dako, Glostrup, Denmark), followed by incubation with an anti-rabbit peroxidase polymer (Nichirei Bioscience). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 2c-f). After treatment at our department, ramucirumab was discontinued due to cancer progression on CT. The patient subsequently received other drugs but died six months after visiting our department; the oral lesions did not recur after the discontinuation of ramucirumab.
Figure 2. Histopathological characteristics of case 1. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) Endothelial cells positive for CD31 (c) and negative for D2-40 (d) can be seen. (e) Strong immunostaining for vascular endothelial growth factor receptor-2 (VEGFR2) can be seen in almost all vascular endothelial cells. (f) Cell proliferation marker Ki-67 is also frequently detected.
Case 2
A 67-year-old man was admitted to our department owing to a tumor on the upper lip. He had been diagnosed with stage IIIB (cT3N3aM0) gastric cancer six years previously, and distal gastrectomy had been performed at the gastrointestinal surgery department of our hospital; S-1 was administered for 1 year as postoperative adjuvant chemotherapy. Four years later, magnetic resonance imaging showed cancerous peritonitis; S-1 was therefore restarted. Owing to the evidence of lesions on a CT examination three months later, XELOX therapy was started. Since disease progression was observed after 22 courses, combination chemotherapy was started with ramucirumab+nab-paclitaxel. In each four-week course, ramucirumab was administered once every two weeks along with nab-paclitaxel for three consecutive weeks and a one-week break. At the end of six courses, CT showed no obvious change in the tumor size and increased ascites; this indicated stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors.
During the fifth course, a tumor appeared on the upper lip. The lip tumor fell off spontaneously but subsequently recurred and increased in size; the patient was therefore referred to our department during the seventh course. On an initial physical examination, a 5-mm elastic soft mass was observed on the right upper lip. In addition, the crown of the upper left central incisor was fractured (Fig. 3a). Oral care was found to be poor, and the periodontal pocket was deep overall, reaching 6 mm at the right maxillary canine. The left maxillary central incisor and lateral incisors showed moderate instability; the mandibular partial denture was not sufficiently stable. Panoramic imaging showed multiple residual roots, with a fracture at the upper right first molar (Fig. 3b). The patient's family had a dental clinic, but he had not undergone intensive treatment after the initiation of anticancer drug therapy. A benign tumor was diagnosed at the upper lip and was excised under local anesthesia; the fractured piece of the upper left central incisor was also removed simultaneously. No abnormal bleeding was observed from the sutures nine days later.
Figure 3. Clinical and imaging characteristics of case 2. (a) Macroscopic findings: a 5-mm extroverted, elastic, soft mass can be seen on the upper right lip. (b) Panoramic image: Moderate to high marginal alveolar bone resorption can be seen. A horizontal root fracture can be seen in the upper first molar (*); both maxillary sinuses are deformed.
The histopathological findings of the oral specimens obtained from the lip tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 4a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 4b). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 4c-f).
Figure 4. Histopathological characteristics of case 2. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) CD31 (c) and D2-40 (d) immunostaining: endothelial cells are positive for CD31 and negative for D2-40. (e) Vascular endothelial growth factor receptor-2 (VEGFR2) immunostaining. Strong staining can be seen in almost all vascular endothelial cells. (f) The Ki-67 cell proliferation marker is also frequently detected in vascular endothelial cells.
After starting treatment, the patient presented with a generalized pruritic skin rash; difluprednate ointment was prescribed. At the same time as the visit to our department, pruritus was observed on the back; a 1-cm tumor also appeared, which required resection at a nearby dermatology clinic. A histopathological examination showed capillary lobular growth with vascular endothelial cell proliferation, suggestive of a pyogenic granuloma. Since exacerbation of the cancerous peritonitis was confirmed on CT after 12 courses, ramucirumab+paclitaxel therapy was discontinued at 6 months after the initial visit to our department, and nivolumab therapy was started. After resection, there was no evidence of recurrence of the oral or skin tumors.
Discussion
To our knowledge, this is the first report concerning the histopathological examination of oral PG in patients receiving ramucirumab. The causes of PG were considered to be the systemic deterioration of the angiogenic balance by ramucirumab and the locally deteriorated oral environment (4). Angiogenesis is an important characteristic of cancer; malignant tumors create new vascular networks to meet their increased demand for oxygen and nutrients and to achieve efficient removal of metabolic waste. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been identified as major regulators of angiogenesis (8,9). VEGFR2 is a major mediator of VEGF-induced angiogenesis and exhibits the most potent tyrosine kinase activity; it is being investigated as a target of anti-angiogenic therapy for cancer (10).
Ramucirumab is a fully human IgG1 monoclonal antibody that selectively binds to the extracellular domain of VEGFR2 (9,11). It is mainly used as a second-line treatment for advanced cancers, such as gastric, colorectal, and non-small-cell lung cancers (11). The Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma trial, which was the first randomized phase III study on advanced gastric cancer, revealed that ramucirumab therapy was beneficial in terms of the overall survival compared with placebo in a second-line treatment setting (8,12). The combination of ramucirumab with paclitaxel significantly increases the overall survival compared with placebo plus paclitaxel in advanced gastric or gastro-esophageal junction adenocarcinoma patients (11,12). Various adverse events have been reported in relation to ramucirumab, including hypertension, deep vein thrombosis, headaches, anorexia, vomiting, and dyspnea (8,11). Interestingly, there are several reports on PGs and hemangiomas occurring in patients receiving ramucirumab. Lim et al. first reported the development of an angioma during the administration of ramucirumab in 2015 (5); several cases have been reported since then, including sporadic and multiple occurrences (5-7); tumors appeared at a minimum of two months and a maximum of six months after starting ramucirumab (5-7). The pathogenesis of ramucirumab-related PG remains unknown. Ibe et al. reported on a case of PG of the fingers, where strongly positive immunostaining was observed for VEGFR2; they hypothesized that following ramucirumab administration, a small wound triggered VEGFR2 overexpression owing to a mutation in KDR (p.T771R), which is a driver of vascular lesions (6).
PG in our two cases developed during the administration of ramucirumab. The tumor appeared during the fourth and sixth course in cases 1 and 2, respectively. From the clinical course, ramucirumab appeared to be involved in the formation of PG. The first case in the oral cavity was sporadic. However, in the second case, PG also developed in the skin of the back; it was therefore considered to be a case of multiple PG. On immunostaining, both cases tested positive for VEGFR2 and CD31, which are expressed in blood vessels; they tested negative for D2-40, which is expressed in lymphatic vessels. The expression of the growth factor Ki-67 was also observed. These results showed that the overexpression of VEGFR2 caused the excessive proliferation of small blood vessels, leading to PG.
The findings from these cases suggest that the oral environment was also involved in PG formation. The oral cavity is easily damaged by caries, periodontal disease, defective teeth or bite, food, and poor oral cleaning. In these two cases, the oral environment was poor, and dental care was insufficient. In addition to the administration of ramucirumab, intraoral stimulation by the residual roots and sharp edges of the dentures were also suspected of having induced the development of PGs.
A limitation of this study is that the frequency of ramucirumab-related PG and the difference in characteristics from other PGs were not determined. Further large-scale studies are needed to elucidate the characteristics and etiology of oral PG in patients treated with ramucirumab. Among the oral adverse events caused by specific drugs used in anticancer treatment, everolimus-related stomatitis and medication-related osteonecrosis of the jaw due to bone resorption inhibitors, such as bisphosphonates and denosumab, are well known. The frequency of ramucirumab-related PG is unknown, but the use of ramucirumab is increasing; the incidence of oral PG is therefore expected to increase in the future. Medical and dental interprofessional collaboration is essential for investigating the possibility of oral PG development during the administration of ramucirumab.
In conclusion, we encountered two cases of ramucirumab-related oral PG. The deterioration in the local angiogenic balance caused by ramucirumab and the poor oral environment contributed to the formation of PG. Oncologists and dentists should carefully consider the development of oral symptoms and their management.
The authors state that they have no Conflict of Interest (COI). | XELOX REGIMEN | DrugDosageText | CC BY-NC-ND | 33678742 | 19,848,146 | 2021-08-15 |
What was the dosage of drug 'PACLITAXEL'? | Ramucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases.
Pyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.
pmcIntroduction
Pyogenic granuloma (PG) is a granulomatous, elevated lesion that occurs on the skin and mucous membranes (1). Clinically, this lesion grows without pain, and frequently appears as a hemorrhagic, red-purple, venous or perforating tumor mass (2). It may grow rapidly, and needs to be differentiated from malignant tumors. PGs are commonly found in the face and limbs. In the oral region, the gingiva, lip, and tongue are common sites (1,3).
PG arises from various stimuli, including chronic low-grade irritation, traumatic injury, hormones, and drugs (1). The pathogenesis of pyogenic granuloma at the molecular level is unclear, but may be considered as resulting from the imbalance of angiogenesis enhancers and inhibitors (4).
It has been reported that PG and angioma can develop during the administration of ramucirumab, an angiogenesis inhibitor (5-7). Most of these reports describe skin lesions, and to our knowledge, no detailed studies have been published on oral lesions, especially from the point of view of histopathology. Therefore, in this study, we report two cases of PG that occurred in the oral cavity during the administration of ramucirumab. The study protocol adhered to the recommendations in the Declaration of Helsinki and the study was approved by the regional Ethical Review Board of our Institution.
Case Report
Case 1
A 55-year-old man presented to our department with swelling of the right tongue. He was diagnosed with stage IV (T4aN2M1) gastric cardia cancer. Combination chemotherapy with capecitabine+cisplatinum+trastuzumab therapy was started; owing to tumor growth, however, chemotherapy was stopped after eight courses, and new combination chemotherapy with ramucirumab+weekly paclitaxel was initiated. In each four-week course, ramucirumab was administered once every two weeks with paclitaxel for three consecutive weeks, with a one-week break. After four courses of treatment, computed tomography (CT) showed that the tumor had shrunk by more than 30%; this indicated a partial response (PR) to treatment according to the Response Evaluation Criteria in Solid Tumors.
After seven courses, a tumor was found on the right tongue. An initial physical examination revealed a 6-mm extroverted, elastic, soft mass (Fig. 1a). The mass was painless and involved the upper and lower canines and premolars. Hemorrhaging was also observed from the gingiva of the lower anterior region, and the crown of the right upper second molar was missing. On panoramic imaging, the upper right maxillary second molar had a residual root (Fig. 1b). The patient had no family dentist and had not received dental care for more than three years. Daily prevention at home was performed only once a day.
Figure 1. Clinical and imaging characteristics of case 1. (a) Macroscopic findings. A pedunculated tumor of approximately 6 mm can be seen on the right side of the tongue. Slight bleeding is seen from the left lower anterior gingiva. (b) Panoramic image: Moderate marginal alveolar bone resorption is seen. The upper right maxillary second molar had a residual root (*).
The tumor showed rapid growth and was therefore resected under local anesthesia; no abnormal bleeding was observed. Histopathological findings of oral specimens obtained from the tongue tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 2a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 2b). For immunostaining, heat-induced antigen retrieval was performed by incubating the sections with 10 mM Tris base containing 1 mM ethylenediaminetetraacetic acid (pH 9.0). In order to detect vascular endothelial growth factor receptor-2 (VEGFR2), CD31, D2-40, and Ki-67, a section was incubated with anti-VEGFR2 rabbit monoclonal antibody (clone 55B11; Cell Signaling Technology, Danvers, USA), anti-CD31 (clone 1aA10; Novocastra Laboratories, Newcastle upon Tyne, UK), anti D2-40 (clone D2-40; Nichirei Bioscience, Tokyo, Japan), and Ki-67 (MIB-1; Dako, Glostrup, Denmark), followed by incubation with an anti-rabbit peroxidase polymer (Nichirei Bioscience). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 2c-f). After treatment at our department, ramucirumab was discontinued due to cancer progression on CT. The patient subsequently received other drugs but died six months after visiting our department; the oral lesions did not recur after the discontinuation of ramucirumab.
Figure 2. Histopathological characteristics of case 1. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) Endothelial cells positive for CD31 (c) and negative for D2-40 (d) can be seen. (e) Strong immunostaining for vascular endothelial growth factor receptor-2 (VEGFR2) can be seen in almost all vascular endothelial cells. (f) Cell proliferation marker Ki-67 is also frequently detected.
Case 2
A 67-year-old man was admitted to our department owing to a tumor on the upper lip. He had been diagnosed with stage IIIB (cT3N3aM0) gastric cancer six years previously, and distal gastrectomy had been performed at the gastrointestinal surgery department of our hospital; S-1 was administered for 1 year as postoperative adjuvant chemotherapy. Four years later, magnetic resonance imaging showed cancerous peritonitis; S-1 was therefore restarted. Owing to the evidence of lesions on a CT examination three months later, XELOX therapy was started. Since disease progression was observed after 22 courses, combination chemotherapy was started with ramucirumab+nab-paclitaxel. In each four-week course, ramucirumab was administered once every two weeks along with nab-paclitaxel for three consecutive weeks and a one-week break. At the end of six courses, CT showed no obvious change in the tumor size and increased ascites; this indicated stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors.
During the fifth course, a tumor appeared on the upper lip. The lip tumor fell off spontaneously but subsequently recurred and increased in size; the patient was therefore referred to our department during the seventh course. On an initial physical examination, a 5-mm elastic soft mass was observed on the right upper lip. In addition, the crown of the upper left central incisor was fractured (Fig. 3a). Oral care was found to be poor, and the periodontal pocket was deep overall, reaching 6 mm at the right maxillary canine. The left maxillary central incisor and lateral incisors showed moderate instability; the mandibular partial denture was not sufficiently stable. Panoramic imaging showed multiple residual roots, with a fracture at the upper right first molar (Fig. 3b). The patient's family had a dental clinic, but he had not undergone intensive treatment after the initiation of anticancer drug therapy. A benign tumor was diagnosed at the upper lip and was excised under local anesthesia; the fractured piece of the upper left central incisor was also removed simultaneously. No abnormal bleeding was observed from the sutures nine days later.
Figure 3. Clinical and imaging characteristics of case 2. (a) Macroscopic findings: a 5-mm extroverted, elastic, soft mass can be seen on the upper right lip. (b) Panoramic image: Moderate to high marginal alveolar bone resorption can be seen. A horizontal root fracture can be seen in the upper first molar (*); both maxillary sinuses are deformed.
The histopathological findings of the oral specimens obtained from the lip tumor revealed local proliferation of vascular endothelial cells in the connective tissue (Fig. 4a). Expanded capillaries and surrounding endothelial cells were also observed (Fig. 4b). Based on the immunostaining results, most blood vessels were considered to be CD31- and VEGFR2-positive and D2-40-negative; Ki-67, a proliferation marker, was also found to be strongly expressed in the nuclei of endothelial cells (Fig. 4c-f).
Figure 4. Histopathological characteristics of case 2. (a, b) Hematoxylin and Eosin staining. a: ×100, b: ×400. A large number of capillaries showing foliar compaction can be seen beneath the mucous membrane. Hemorrhaging and slight inflammatory cell infiltration can be seen in the stroma. No malignant cells are observed; the findings are consistent with those of pyogenic granuloma. (c, d) CD31 (c) and D2-40 (d) immunostaining: endothelial cells are positive for CD31 and negative for D2-40. (e) Vascular endothelial growth factor receptor-2 (VEGFR2) immunostaining. Strong staining can be seen in almost all vascular endothelial cells. (f) The Ki-67 cell proliferation marker is also frequently detected in vascular endothelial cells.
After starting treatment, the patient presented with a generalized pruritic skin rash; difluprednate ointment was prescribed. At the same time as the visit to our department, pruritus was observed on the back; a 1-cm tumor also appeared, which required resection at a nearby dermatology clinic. A histopathological examination showed capillary lobular growth with vascular endothelial cell proliferation, suggestive of a pyogenic granuloma. Since exacerbation of the cancerous peritonitis was confirmed on CT after 12 courses, ramucirumab+paclitaxel therapy was discontinued at 6 months after the initial visit to our department, and nivolumab therapy was started. After resection, there was no evidence of recurrence of the oral or skin tumors.
Discussion
To our knowledge, this is the first report concerning the histopathological examination of oral PG in patients receiving ramucirumab. The causes of PG were considered to be the systemic deterioration of the angiogenic balance by ramucirumab and the locally deteriorated oral environment (4). Angiogenesis is an important characteristic of cancer; malignant tumors create new vascular networks to meet their increased demand for oxygen and nutrients and to achieve efficient removal of metabolic waste. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been identified as major regulators of angiogenesis (8,9). VEGFR2 is a major mediator of VEGF-induced angiogenesis and exhibits the most potent tyrosine kinase activity; it is being investigated as a target of anti-angiogenic therapy for cancer (10).
Ramucirumab is a fully human IgG1 monoclonal antibody that selectively binds to the extracellular domain of VEGFR2 (9,11). It is mainly used as a second-line treatment for advanced cancers, such as gastric, colorectal, and non-small-cell lung cancers (11). The Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma trial, which was the first randomized phase III study on advanced gastric cancer, revealed that ramucirumab therapy was beneficial in terms of the overall survival compared with placebo in a second-line treatment setting (8,12). The combination of ramucirumab with paclitaxel significantly increases the overall survival compared with placebo plus paclitaxel in advanced gastric or gastro-esophageal junction adenocarcinoma patients (11,12). Various adverse events have been reported in relation to ramucirumab, including hypertension, deep vein thrombosis, headaches, anorexia, vomiting, and dyspnea (8,11). Interestingly, there are several reports on PGs and hemangiomas occurring in patients receiving ramucirumab. Lim et al. first reported the development of an angioma during the administration of ramucirumab in 2015 (5); several cases have been reported since then, including sporadic and multiple occurrences (5-7); tumors appeared at a minimum of two months and a maximum of six months after starting ramucirumab (5-7). The pathogenesis of ramucirumab-related PG remains unknown. Ibe et al. reported on a case of PG of the fingers, where strongly positive immunostaining was observed for VEGFR2; they hypothesized that following ramucirumab administration, a small wound triggered VEGFR2 overexpression owing to a mutation in KDR (p.T771R), which is a driver of vascular lesions (6).
PG in our two cases developed during the administration of ramucirumab. The tumor appeared during the fourth and sixth course in cases 1 and 2, respectively. From the clinical course, ramucirumab appeared to be involved in the formation of PG. The first case in the oral cavity was sporadic. However, in the second case, PG also developed in the skin of the back; it was therefore considered to be a case of multiple PG. On immunostaining, both cases tested positive for VEGFR2 and CD31, which are expressed in blood vessels; they tested negative for D2-40, which is expressed in lymphatic vessels. The expression of the growth factor Ki-67 was also observed. These results showed that the overexpression of VEGFR2 caused the excessive proliferation of small blood vessels, leading to PG.
The findings from these cases suggest that the oral environment was also involved in PG formation. The oral cavity is easily damaged by caries, periodontal disease, defective teeth or bite, food, and poor oral cleaning. In these two cases, the oral environment was poor, and dental care was insufficient. In addition to the administration of ramucirumab, intraoral stimulation by the residual roots and sharp edges of the dentures were also suspected of having induced the development of PGs.
A limitation of this study is that the frequency of ramucirumab-related PG and the difference in characteristics from other PGs were not determined. Further large-scale studies are needed to elucidate the characteristics and etiology of oral PG in patients treated with ramucirumab. Among the oral adverse events caused by specific drugs used in anticancer treatment, everolimus-related stomatitis and medication-related osteonecrosis of the jaw due to bone resorption inhibitors, such as bisphosphonates and denosumab, are well known. The frequency of ramucirumab-related PG is unknown, but the use of ramucirumab is increasing; the incidence of oral PG is therefore expected to increase in the future. Medical and dental interprofessional collaboration is essential for investigating the possibility of oral PG development during the administration of ramucirumab.
In conclusion, we encountered two cases of ramucirumab-related oral PG. The deterioration in the local angiogenic balance caused by ramucirumab and the poor oral environment contributed to the formation of PG. Oncologists and dentists should carefully consider the development of oral symptoms and their management.
The authors state that they have no Conflict of Interest (COI). | WEEKLY | DrugDosageText | CC BY-NC-ND | 33678742 | 19,848,131 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myokymia'. | Eribulin Mesylate-related Multifocal Demyelinating Neuropathy with Myokymia in a Breast Cancer Patient.
We herein report a 48-year-old woman receiving eribulin mesylate for breast cancer who presented with gait disorder, distal limb paresthesia, and weakness progressing monthly. A nerve conduction study indicated demyelination with multifocal conduction block. Considering the immune-mediated pathology of her condition, she was administered intravenous immunoglobulin. Her neurological symptoms improved promptly after intravenous immunoglobulin therapy and eribulin withdrawal. Furthermore, the limb myokymia seen at the time of admission disappeared. Her symptoms continued to improve without additional treatment. We conclude that eribulin was a rare cause of demyelinating neuropathy with multifocal conduction block derived from immune-mediated pathology.
pmcIntroduction
Eribulin mesylate is a microtubule inhibitor used to treat recurrent breast cancer and malignant soft tissue tumors. Neuropathy is reported to be a common side effect of eribulin (1,2). Peripheral neuropathy secondary to microtubule inhibitors usually causes distal limb paresthesia with a characteristic “stocking-glove” distribution, suggesting length-dependent obstacles caused by the disruption of microtubule-dependent transport (3). The main mechanism underlying microtubule inhibitors-related neuropathy has been reported to be axonal injury, and there are no reports of the frequency of demyelination with conduction block (4).
We herein report a woman who experienced reversible demyelinating neuropathy with multifocal conduction block and myokymia that instantly improved on receiving intravenous immunoglobulin and the withdrawal of eribulin, suggesting an immunological mechanism underlying eribulin-related neuropathy.
Case Report
A 48-year-old woman with breast cancer was admitted to our department in May 2020 with a chief complaint of gait disorder. She had been treated with tamoxifen, trastuzumab, pertuzumab, and denosumab for cervical metastasis (C5-6) from May 2018 onwards. Tamoxifen was replaced with eribulin (2 mg per week, for 2 of every 3 weeks) in March 2019 due to the expansion of the primary lesion and increase in tumor markers. In July 2019, she experienced upper limb clumsiness and lower limb paresthesia; subsequently, she noticed gait unsteadiness in December 2019. Since the symptoms were initially thought to be due to compression of the cervical spinal cord, she underwent posterior cervical spinal fusion in January 2020; however, her symptoms worsened despite the surgery. Her gait disorder progressed weekly, and eventually she became unable to walk. She had no medical history other than breast cancer and a family history of neurological disorders.
An examination on admission revealed that the patient had asymmetric limb weakness, especially in the proximal right upper limb and both distal lower limbs, diminished deep tendon reflexes, and paresthesia of the right palm, left first-third fingers, and lower legs. Her vibration sensation of the lower limbs was severely impaired, and she was unable to walk due to ataxia. We also found intermittent myokymic movements on her forearms and lower legs.
Her nerve conduction studies (NCSs) showed decreased conduction velocities and temporal dispersion in all of the motor nerves that were analyzed (Fig. 1). The NCS findings were also characterized by asymmetrical and multifocal conduction block, with most distal amplitudes being normal. An electrodiagnostic inching study on the left median nerve showed conduction block on the proximal forearm (elbow-9 cm). In the F-wave test, A waves were observed on the median, ulnar, and tibial nerves (Fig. 2). The sensory nerve action potential of the median and ulnar nerves also showed temporal dispersion at the same segment as the motor nerves involved (Fig. 3).
Figure 1. The motor nerve conduction study on admission. Temporal dispersion and decreased conduction velocities indicating demyelination were observed. Multifocal asymmetrical conduction block was seen on the forearm and lower leg. B.Elbow: below elbow, A.Elbow: above elbow, Popliteal F.: popliteal fossa
Figure 2. Left median nerve inching test and F wave test. Conduction block was found 9 cm distal to the left elbow. A wave was observed on both the median nerves.
Figure 3. The sensory nerve conduction study on admission. Right median and ulnar nerves showed temporal dispersion at the same segment of the motor nerves involved. B.Elbow: below elbow, A.Elbow: above elbow, SNAP: sensory nerve action potential
The blood tests did not detect monoclonal immunoglobulin, anti-ganglioside antibodies (IgG and IgM for GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, Gal-C and GalNAc-GD1a, IgG for GD1a/GD1b), anti-neurofascin 155 antibody, or anti-contactin-1 antibody. Carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels were within the normal range (<4.9 ng/mL, <26.9 U/mL). The cerebrospinal fluid test showed no increase in protein levels (22 mg/dL) or cell counts (0/μL).
Furthermore, cervical magnetic resonance imaging (MRI) did not suggest progression of the spinal cord compression, and lumber MRI showed no enlargement or contrast enhancement of the lumbar plexus. Needle electromyography showed fasciculation potentials, myokymic discharges, and large polyphasic motor unit potentials on her right abductor pollicis brevis, left quadriceps, and left peroneus longus; however, there were no fibrillation potentials or positive sharp waves at rest. A neuromuscular echogram revealed frequent fasciculation and myokymia on limb muscles, but there was no change in nerve diameter in the area where the conduction block was observed.
We considered multifocal acquired demyelinating sensory and motor (MADSAM)-type chronic inflammatory demyelinating polyneuropathy (CIDP), eribulin-related chemotherapy-induced neuropathy, and paraneoplastic neuropathy as the differential diagnoses.
We started intravenous immunoglobulin (IVIG) 400 mg/kg for 5 days, assuming the immune-mediated pathology of her condition. Within two weeks, the ataxia and muscle strength of the distal lower limbs improved, accompanying a decrease in the frequency of myokymia, and the patient started walking more stably. Eribulin was discontinued because of suspicion of association with neuropathy. She was discharged on the 23rd day of admission. During outpatient follow-up, we noted that her gait improved monthly without the need for additional treatments. NCSs performed two months later showed no significant improvement, but neuromuscular echography showed that the limb myokymia had almost disappeared.
Discussion
Eribulin mesylate, an inhibitor of microtubule dynamics, was synthesized with reference to a natural substance called halichondrin B1 extracted from the marine organism halichondria (1). A previous study reported that the incidence of peripheral neuropathy with eribulin treatment was 35%, which was the most common adverse event leading to the discontinuation of eribulin (1). Other microtubule inhibitors, such as vincristine and paclitaxel, also cause neuropathy, the main mechanism of which is axonopathy (5). However, the present case of eribulin-related neuropathy was characterized by 1) multifocal demyelinating neuropathy with conduction block, 2) myokymia, and 3) responsiveness to immunotherapy. To our knowledge, there has only been one other case report on demyelinating neuropathy after the administration of eribulin, wherein the patient presented with multifocal conduction block and myokymia, similar to our case (6). However, that case involved no immunotherapy intervention, or apparent improvement in the symptoms, and the patient ultimately passed away from breast cancer progression within half a year.
Our case of eribulin-related neuropathy showed prominent multifocal demyelination, with NCS findings consistent with MADSAM-type CIDP. MADSAM is characterized by multifocal conduction block in the intermediate nerve trunk, the mechanism of which is speculated to be cell-mediated immunity (7), along with a poorer responsiveness to immunoglobulin and plasmapheresis than typical CIDP (8). Our case was distinguished from MADSAM in that the patient was clearly responsive to immunotherapy and kept improving without additional treatment. Although we did not perform a nerve biopsy, resulting in an insufficient pathological evaluation, the prompt response to IVIG in our case suggested that eribulin administration caused secondary immune-mediated neuropathy involving a mechanism different from MADSAM.
The disappearance of myokymia in the lower extremities after the administration of immunotherapy was another characteristic feature of our case. Limb myokymia has been reported in other demyelinating peripheral nerve disorders, such as Guillain-Barre syndrome (9,10) and CIDP (11,12). MMN also presents fasciculation and myokymia (13) but differs from our case in that it does not show sensory nerve damage. Gerard and Michel reported that conduction blocks lasting more than three months show fasciculation potentials and sometimes even myokymic discharges (14). A few earlier studies mentioned the relationship between axonal hyperpolarization distal to the site of the conduction block and myokymia (15,16). Myokymia disappeared in our patient along with the improvement in other clinical symptoms after the initiation of immunotherapy. Although eribulin-related demyelinating neuropathy is rarely reported, and the detailed mechanism is unclear, the fact that myokymia was a characteristic finding in both the previously reported case (6) and our own suggests that demyelination involving conduction block secondary to eribulin administration may present with unknown pathophysiological conditions related to myokiymia.
In conclusion, it can be inferred from the present case that eribulin can cause demyelinating neuropathy and requires differentiation from other acquired demyelinating neuropathies. If the neuropathy is severe, not only the discontinuation of eribulin but also intervention with immunotherapy may be effective. Further research concerning the detailed mechanism underlying eribulin-induced neuropathy is warranted.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We are grateful to Makoto Samukawa, Susumu Kusunoki (Department of Neurology, Kindai University, Faculty of Medicine), Ryo Yamasaki and Hidenori Ogata (Department of Neurology, Kyusyu University, Faculty of Medicine) for their excellent technical assistance. | ERIBULIN | DrugsGivenReaction | CC BY-NC-ND | 33678744 | 19,840,712 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nerve conduction studies abnormal'. | Eribulin Mesylate-related Multifocal Demyelinating Neuropathy with Myokymia in a Breast Cancer Patient.
We herein report a 48-year-old woman receiving eribulin mesylate for breast cancer who presented with gait disorder, distal limb paresthesia, and weakness progressing monthly. A nerve conduction study indicated demyelination with multifocal conduction block. Considering the immune-mediated pathology of her condition, she was administered intravenous immunoglobulin. Her neurological symptoms improved promptly after intravenous immunoglobulin therapy and eribulin withdrawal. Furthermore, the limb myokymia seen at the time of admission disappeared. Her symptoms continued to improve without additional treatment. We conclude that eribulin was a rare cause of demyelinating neuropathy with multifocal conduction block derived from immune-mediated pathology.
pmcIntroduction
Eribulin mesylate is a microtubule inhibitor used to treat recurrent breast cancer and malignant soft tissue tumors. Neuropathy is reported to be a common side effect of eribulin (1,2). Peripheral neuropathy secondary to microtubule inhibitors usually causes distal limb paresthesia with a characteristic “stocking-glove” distribution, suggesting length-dependent obstacles caused by the disruption of microtubule-dependent transport (3). The main mechanism underlying microtubule inhibitors-related neuropathy has been reported to be axonal injury, and there are no reports of the frequency of demyelination with conduction block (4).
We herein report a woman who experienced reversible demyelinating neuropathy with multifocal conduction block and myokymia that instantly improved on receiving intravenous immunoglobulin and the withdrawal of eribulin, suggesting an immunological mechanism underlying eribulin-related neuropathy.
Case Report
A 48-year-old woman with breast cancer was admitted to our department in May 2020 with a chief complaint of gait disorder. She had been treated with tamoxifen, trastuzumab, pertuzumab, and denosumab for cervical metastasis (C5-6) from May 2018 onwards. Tamoxifen was replaced with eribulin (2 mg per week, for 2 of every 3 weeks) in March 2019 due to the expansion of the primary lesion and increase in tumor markers. In July 2019, she experienced upper limb clumsiness and lower limb paresthesia; subsequently, she noticed gait unsteadiness in December 2019. Since the symptoms were initially thought to be due to compression of the cervical spinal cord, she underwent posterior cervical spinal fusion in January 2020; however, her symptoms worsened despite the surgery. Her gait disorder progressed weekly, and eventually she became unable to walk. She had no medical history other than breast cancer and a family history of neurological disorders.
An examination on admission revealed that the patient had asymmetric limb weakness, especially in the proximal right upper limb and both distal lower limbs, diminished deep tendon reflexes, and paresthesia of the right palm, left first-third fingers, and lower legs. Her vibration sensation of the lower limbs was severely impaired, and she was unable to walk due to ataxia. We also found intermittent myokymic movements on her forearms and lower legs.
Her nerve conduction studies (NCSs) showed decreased conduction velocities and temporal dispersion in all of the motor nerves that were analyzed (Fig. 1). The NCS findings were also characterized by asymmetrical and multifocal conduction block, with most distal amplitudes being normal. An electrodiagnostic inching study on the left median nerve showed conduction block on the proximal forearm (elbow-9 cm). In the F-wave test, A waves were observed on the median, ulnar, and tibial nerves (Fig. 2). The sensory nerve action potential of the median and ulnar nerves also showed temporal dispersion at the same segment as the motor nerves involved (Fig. 3).
Figure 1. The motor nerve conduction study on admission. Temporal dispersion and decreased conduction velocities indicating demyelination were observed. Multifocal asymmetrical conduction block was seen on the forearm and lower leg. B.Elbow: below elbow, A.Elbow: above elbow, Popliteal F.: popliteal fossa
Figure 2. Left median nerve inching test and F wave test. Conduction block was found 9 cm distal to the left elbow. A wave was observed on both the median nerves.
Figure 3. The sensory nerve conduction study on admission. Right median and ulnar nerves showed temporal dispersion at the same segment of the motor nerves involved. B.Elbow: below elbow, A.Elbow: above elbow, SNAP: sensory nerve action potential
The blood tests did not detect monoclonal immunoglobulin, anti-ganglioside antibodies (IgG and IgM for GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, Gal-C and GalNAc-GD1a, IgG for GD1a/GD1b), anti-neurofascin 155 antibody, or anti-contactin-1 antibody. Carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels were within the normal range (<4.9 ng/mL, <26.9 U/mL). The cerebrospinal fluid test showed no increase in protein levels (22 mg/dL) or cell counts (0/μL).
Furthermore, cervical magnetic resonance imaging (MRI) did not suggest progression of the spinal cord compression, and lumber MRI showed no enlargement or contrast enhancement of the lumbar plexus. Needle electromyography showed fasciculation potentials, myokymic discharges, and large polyphasic motor unit potentials on her right abductor pollicis brevis, left quadriceps, and left peroneus longus; however, there were no fibrillation potentials or positive sharp waves at rest. A neuromuscular echogram revealed frequent fasciculation and myokymia on limb muscles, but there was no change in nerve diameter in the area where the conduction block was observed.
We considered multifocal acquired demyelinating sensory and motor (MADSAM)-type chronic inflammatory demyelinating polyneuropathy (CIDP), eribulin-related chemotherapy-induced neuropathy, and paraneoplastic neuropathy as the differential diagnoses.
We started intravenous immunoglobulin (IVIG) 400 mg/kg for 5 days, assuming the immune-mediated pathology of her condition. Within two weeks, the ataxia and muscle strength of the distal lower limbs improved, accompanying a decrease in the frequency of myokymia, and the patient started walking more stably. Eribulin was discontinued because of suspicion of association with neuropathy. She was discharged on the 23rd day of admission. During outpatient follow-up, we noted that her gait improved monthly without the need for additional treatments. NCSs performed two months later showed no significant improvement, but neuromuscular echography showed that the limb myokymia had almost disappeared.
Discussion
Eribulin mesylate, an inhibitor of microtubule dynamics, was synthesized with reference to a natural substance called halichondrin B1 extracted from the marine organism halichondria (1). A previous study reported that the incidence of peripheral neuropathy with eribulin treatment was 35%, which was the most common adverse event leading to the discontinuation of eribulin (1). Other microtubule inhibitors, such as vincristine and paclitaxel, also cause neuropathy, the main mechanism of which is axonopathy (5). However, the present case of eribulin-related neuropathy was characterized by 1) multifocal demyelinating neuropathy with conduction block, 2) myokymia, and 3) responsiveness to immunotherapy. To our knowledge, there has only been one other case report on demyelinating neuropathy after the administration of eribulin, wherein the patient presented with multifocal conduction block and myokymia, similar to our case (6). However, that case involved no immunotherapy intervention, or apparent improvement in the symptoms, and the patient ultimately passed away from breast cancer progression within half a year.
Our case of eribulin-related neuropathy showed prominent multifocal demyelination, with NCS findings consistent with MADSAM-type CIDP. MADSAM is characterized by multifocal conduction block in the intermediate nerve trunk, the mechanism of which is speculated to be cell-mediated immunity (7), along with a poorer responsiveness to immunoglobulin and plasmapheresis than typical CIDP (8). Our case was distinguished from MADSAM in that the patient was clearly responsive to immunotherapy and kept improving without additional treatment. Although we did not perform a nerve biopsy, resulting in an insufficient pathological evaluation, the prompt response to IVIG in our case suggested that eribulin administration caused secondary immune-mediated neuropathy involving a mechanism different from MADSAM.
The disappearance of myokymia in the lower extremities after the administration of immunotherapy was another characteristic feature of our case. Limb myokymia has been reported in other demyelinating peripheral nerve disorders, such as Guillain-Barre syndrome (9,10) and CIDP (11,12). MMN also presents fasciculation and myokymia (13) but differs from our case in that it does not show sensory nerve damage. Gerard and Michel reported that conduction blocks lasting more than three months show fasciculation potentials and sometimes even myokymic discharges (14). A few earlier studies mentioned the relationship between axonal hyperpolarization distal to the site of the conduction block and myokymia (15,16). Myokymia disappeared in our patient along with the improvement in other clinical symptoms after the initiation of immunotherapy. Although eribulin-related demyelinating neuropathy is rarely reported, and the detailed mechanism is unclear, the fact that myokymia was a characteristic finding in both the previously reported case (6) and our own suggests that demyelination involving conduction block secondary to eribulin administration may present with unknown pathophysiological conditions related to myokiymia.
In conclusion, it can be inferred from the present case that eribulin can cause demyelinating neuropathy and requires differentiation from other acquired demyelinating neuropathies. If the neuropathy is severe, not only the discontinuation of eribulin but also intervention with immunotherapy may be effective. Further research concerning the detailed mechanism underlying eribulin-induced neuropathy is warranted.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We are grateful to Makoto Samukawa, Susumu Kusunoki (Department of Neurology, Kindai University, Faculty of Medicine), Ryo Yamasaki and Hidenori Ogata (Department of Neurology, Kyusyu University, Faculty of Medicine) for their excellent technical assistance. | ERIBULIN | DrugsGivenReaction | CC BY-NC-ND | 33678744 | 19,840,712 | 2021-08-15 |
What was the administration route of drug 'ERIBULIN'? | Eribulin Mesylate-related Multifocal Demyelinating Neuropathy with Myokymia in a Breast Cancer Patient.
We herein report a 48-year-old woman receiving eribulin mesylate for breast cancer who presented with gait disorder, distal limb paresthesia, and weakness progressing monthly. A nerve conduction study indicated demyelination with multifocal conduction block. Considering the immune-mediated pathology of her condition, she was administered intravenous immunoglobulin. Her neurological symptoms improved promptly after intravenous immunoglobulin therapy and eribulin withdrawal. Furthermore, the limb myokymia seen at the time of admission disappeared. Her symptoms continued to improve without additional treatment. We conclude that eribulin was a rare cause of demyelinating neuropathy with multifocal conduction block derived from immune-mediated pathology.
pmcIntroduction
Eribulin mesylate is a microtubule inhibitor used to treat recurrent breast cancer and malignant soft tissue tumors. Neuropathy is reported to be a common side effect of eribulin (1,2). Peripheral neuropathy secondary to microtubule inhibitors usually causes distal limb paresthesia with a characteristic “stocking-glove” distribution, suggesting length-dependent obstacles caused by the disruption of microtubule-dependent transport (3). The main mechanism underlying microtubule inhibitors-related neuropathy has been reported to be axonal injury, and there are no reports of the frequency of demyelination with conduction block (4).
We herein report a woman who experienced reversible demyelinating neuropathy with multifocal conduction block and myokymia that instantly improved on receiving intravenous immunoglobulin and the withdrawal of eribulin, suggesting an immunological mechanism underlying eribulin-related neuropathy.
Case Report
A 48-year-old woman with breast cancer was admitted to our department in May 2020 with a chief complaint of gait disorder. She had been treated with tamoxifen, trastuzumab, pertuzumab, and denosumab for cervical metastasis (C5-6) from May 2018 onwards. Tamoxifen was replaced with eribulin (2 mg per week, for 2 of every 3 weeks) in March 2019 due to the expansion of the primary lesion and increase in tumor markers. In July 2019, she experienced upper limb clumsiness and lower limb paresthesia; subsequently, she noticed gait unsteadiness in December 2019. Since the symptoms were initially thought to be due to compression of the cervical spinal cord, she underwent posterior cervical spinal fusion in January 2020; however, her symptoms worsened despite the surgery. Her gait disorder progressed weekly, and eventually she became unable to walk. She had no medical history other than breast cancer and a family history of neurological disorders.
An examination on admission revealed that the patient had asymmetric limb weakness, especially in the proximal right upper limb and both distal lower limbs, diminished deep tendon reflexes, and paresthesia of the right palm, left first-third fingers, and lower legs. Her vibration sensation of the lower limbs was severely impaired, and she was unable to walk due to ataxia. We also found intermittent myokymic movements on her forearms and lower legs.
Her nerve conduction studies (NCSs) showed decreased conduction velocities and temporal dispersion in all of the motor nerves that were analyzed (Fig. 1). The NCS findings were also characterized by asymmetrical and multifocal conduction block, with most distal amplitudes being normal. An electrodiagnostic inching study on the left median nerve showed conduction block on the proximal forearm (elbow-9 cm). In the F-wave test, A waves were observed on the median, ulnar, and tibial nerves (Fig. 2). The sensory nerve action potential of the median and ulnar nerves also showed temporal dispersion at the same segment as the motor nerves involved (Fig. 3).
Figure 1. The motor nerve conduction study on admission. Temporal dispersion and decreased conduction velocities indicating demyelination were observed. Multifocal asymmetrical conduction block was seen on the forearm and lower leg. B.Elbow: below elbow, A.Elbow: above elbow, Popliteal F.: popliteal fossa
Figure 2. Left median nerve inching test and F wave test. Conduction block was found 9 cm distal to the left elbow. A wave was observed on both the median nerves.
Figure 3. The sensory nerve conduction study on admission. Right median and ulnar nerves showed temporal dispersion at the same segment of the motor nerves involved. B.Elbow: below elbow, A.Elbow: above elbow, SNAP: sensory nerve action potential
The blood tests did not detect monoclonal immunoglobulin, anti-ganglioside antibodies (IgG and IgM for GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, Gal-C and GalNAc-GD1a, IgG for GD1a/GD1b), anti-neurofascin 155 antibody, or anti-contactin-1 antibody. Carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels were within the normal range (<4.9 ng/mL, <26.9 U/mL). The cerebrospinal fluid test showed no increase in protein levels (22 mg/dL) or cell counts (0/μL).
Furthermore, cervical magnetic resonance imaging (MRI) did not suggest progression of the spinal cord compression, and lumber MRI showed no enlargement or contrast enhancement of the lumbar plexus. Needle electromyography showed fasciculation potentials, myokymic discharges, and large polyphasic motor unit potentials on her right abductor pollicis brevis, left quadriceps, and left peroneus longus; however, there were no fibrillation potentials or positive sharp waves at rest. A neuromuscular echogram revealed frequent fasciculation and myokymia on limb muscles, but there was no change in nerve diameter in the area where the conduction block was observed.
We considered multifocal acquired demyelinating sensory and motor (MADSAM)-type chronic inflammatory demyelinating polyneuropathy (CIDP), eribulin-related chemotherapy-induced neuropathy, and paraneoplastic neuropathy as the differential diagnoses.
We started intravenous immunoglobulin (IVIG) 400 mg/kg for 5 days, assuming the immune-mediated pathology of her condition. Within two weeks, the ataxia and muscle strength of the distal lower limbs improved, accompanying a decrease in the frequency of myokymia, and the patient started walking more stably. Eribulin was discontinued because of suspicion of association with neuropathy. She was discharged on the 23rd day of admission. During outpatient follow-up, we noted that her gait improved monthly without the need for additional treatments. NCSs performed two months later showed no significant improvement, but neuromuscular echography showed that the limb myokymia had almost disappeared.
Discussion
Eribulin mesylate, an inhibitor of microtubule dynamics, was synthesized with reference to a natural substance called halichondrin B1 extracted from the marine organism halichondria (1). A previous study reported that the incidence of peripheral neuropathy with eribulin treatment was 35%, which was the most common adverse event leading to the discontinuation of eribulin (1). Other microtubule inhibitors, such as vincristine and paclitaxel, also cause neuropathy, the main mechanism of which is axonopathy (5). However, the present case of eribulin-related neuropathy was characterized by 1) multifocal demyelinating neuropathy with conduction block, 2) myokymia, and 3) responsiveness to immunotherapy. To our knowledge, there has only been one other case report on demyelinating neuropathy after the administration of eribulin, wherein the patient presented with multifocal conduction block and myokymia, similar to our case (6). However, that case involved no immunotherapy intervention, or apparent improvement in the symptoms, and the patient ultimately passed away from breast cancer progression within half a year.
Our case of eribulin-related neuropathy showed prominent multifocal demyelination, with NCS findings consistent with MADSAM-type CIDP. MADSAM is characterized by multifocal conduction block in the intermediate nerve trunk, the mechanism of which is speculated to be cell-mediated immunity (7), along with a poorer responsiveness to immunoglobulin and plasmapheresis than typical CIDP (8). Our case was distinguished from MADSAM in that the patient was clearly responsive to immunotherapy and kept improving without additional treatment. Although we did not perform a nerve biopsy, resulting in an insufficient pathological evaluation, the prompt response to IVIG in our case suggested that eribulin administration caused secondary immune-mediated neuropathy involving a mechanism different from MADSAM.
The disappearance of myokymia in the lower extremities after the administration of immunotherapy was another characteristic feature of our case. Limb myokymia has been reported in other demyelinating peripheral nerve disorders, such as Guillain-Barre syndrome (9,10) and CIDP (11,12). MMN also presents fasciculation and myokymia (13) but differs from our case in that it does not show sensory nerve damage. Gerard and Michel reported that conduction blocks lasting more than three months show fasciculation potentials and sometimes even myokymic discharges (14). A few earlier studies mentioned the relationship between axonal hyperpolarization distal to the site of the conduction block and myokymia (15,16). Myokymia disappeared in our patient along with the improvement in other clinical symptoms after the initiation of immunotherapy. Although eribulin-related demyelinating neuropathy is rarely reported, and the detailed mechanism is unclear, the fact that myokymia was a characteristic finding in both the previously reported case (6) and our own suggests that demyelination involving conduction block secondary to eribulin administration may present with unknown pathophysiological conditions related to myokiymia.
In conclusion, it can be inferred from the present case that eribulin can cause demyelinating neuropathy and requires differentiation from other acquired demyelinating neuropathies. If the neuropathy is severe, not only the discontinuation of eribulin but also intervention with immunotherapy may be effective. Further research concerning the detailed mechanism underlying eribulin-induced neuropathy is warranted.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We are grateful to Makoto Samukawa, Susumu Kusunoki (Department of Neurology, Kindai University, Faculty of Medicine), Ryo Yamasaki and Hidenori Ogata (Department of Neurology, Kyusyu University, Faculty of Medicine) for their excellent technical assistance. | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33678744 | 19,840,712 | 2021-08-15 |
What was the outcome of reaction 'Myokymia'? | Eribulin Mesylate-related Multifocal Demyelinating Neuropathy with Myokymia in a Breast Cancer Patient.
We herein report a 48-year-old woman receiving eribulin mesylate for breast cancer who presented with gait disorder, distal limb paresthesia, and weakness progressing monthly. A nerve conduction study indicated demyelination with multifocal conduction block. Considering the immune-mediated pathology of her condition, she was administered intravenous immunoglobulin. Her neurological symptoms improved promptly after intravenous immunoglobulin therapy and eribulin withdrawal. Furthermore, the limb myokymia seen at the time of admission disappeared. Her symptoms continued to improve without additional treatment. We conclude that eribulin was a rare cause of demyelinating neuropathy with multifocal conduction block derived from immune-mediated pathology.
pmcIntroduction
Eribulin mesylate is a microtubule inhibitor used to treat recurrent breast cancer and malignant soft tissue tumors. Neuropathy is reported to be a common side effect of eribulin (1,2). Peripheral neuropathy secondary to microtubule inhibitors usually causes distal limb paresthesia with a characteristic “stocking-glove” distribution, suggesting length-dependent obstacles caused by the disruption of microtubule-dependent transport (3). The main mechanism underlying microtubule inhibitors-related neuropathy has been reported to be axonal injury, and there are no reports of the frequency of demyelination with conduction block (4).
We herein report a woman who experienced reversible demyelinating neuropathy with multifocal conduction block and myokymia that instantly improved on receiving intravenous immunoglobulin and the withdrawal of eribulin, suggesting an immunological mechanism underlying eribulin-related neuropathy.
Case Report
A 48-year-old woman with breast cancer was admitted to our department in May 2020 with a chief complaint of gait disorder. She had been treated with tamoxifen, trastuzumab, pertuzumab, and denosumab for cervical metastasis (C5-6) from May 2018 onwards. Tamoxifen was replaced with eribulin (2 mg per week, for 2 of every 3 weeks) in March 2019 due to the expansion of the primary lesion and increase in tumor markers. In July 2019, she experienced upper limb clumsiness and lower limb paresthesia; subsequently, she noticed gait unsteadiness in December 2019. Since the symptoms were initially thought to be due to compression of the cervical spinal cord, she underwent posterior cervical spinal fusion in January 2020; however, her symptoms worsened despite the surgery. Her gait disorder progressed weekly, and eventually she became unable to walk. She had no medical history other than breast cancer and a family history of neurological disorders.
An examination on admission revealed that the patient had asymmetric limb weakness, especially in the proximal right upper limb and both distal lower limbs, diminished deep tendon reflexes, and paresthesia of the right palm, left first-third fingers, and lower legs. Her vibration sensation of the lower limbs was severely impaired, and she was unable to walk due to ataxia. We also found intermittent myokymic movements on her forearms and lower legs.
Her nerve conduction studies (NCSs) showed decreased conduction velocities and temporal dispersion in all of the motor nerves that were analyzed (Fig. 1). The NCS findings were also characterized by asymmetrical and multifocal conduction block, with most distal amplitudes being normal. An electrodiagnostic inching study on the left median nerve showed conduction block on the proximal forearm (elbow-9 cm). In the F-wave test, A waves were observed on the median, ulnar, and tibial nerves (Fig. 2). The sensory nerve action potential of the median and ulnar nerves also showed temporal dispersion at the same segment as the motor nerves involved (Fig. 3).
Figure 1. The motor nerve conduction study on admission. Temporal dispersion and decreased conduction velocities indicating demyelination were observed. Multifocal asymmetrical conduction block was seen on the forearm and lower leg. B.Elbow: below elbow, A.Elbow: above elbow, Popliteal F.: popliteal fossa
Figure 2. Left median nerve inching test and F wave test. Conduction block was found 9 cm distal to the left elbow. A wave was observed on both the median nerves.
Figure 3. The sensory nerve conduction study on admission. Right median and ulnar nerves showed temporal dispersion at the same segment of the motor nerves involved. B.Elbow: below elbow, A.Elbow: above elbow, SNAP: sensory nerve action potential
The blood tests did not detect monoclonal immunoglobulin, anti-ganglioside antibodies (IgG and IgM for GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, Gal-C and GalNAc-GD1a, IgG for GD1a/GD1b), anti-neurofascin 155 antibody, or anti-contactin-1 antibody. Carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels were within the normal range (<4.9 ng/mL, <26.9 U/mL). The cerebrospinal fluid test showed no increase in protein levels (22 mg/dL) or cell counts (0/μL).
Furthermore, cervical magnetic resonance imaging (MRI) did not suggest progression of the spinal cord compression, and lumber MRI showed no enlargement or contrast enhancement of the lumbar plexus. Needle electromyography showed fasciculation potentials, myokymic discharges, and large polyphasic motor unit potentials on her right abductor pollicis brevis, left quadriceps, and left peroneus longus; however, there were no fibrillation potentials or positive sharp waves at rest. A neuromuscular echogram revealed frequent fasciculation and myokymia on limb muscles, but there was no change in nerve diameter in the area where the conduction block was observed.
We considered multifocal acquired demyelinating sensory and motor (MADSAM)-type chronic inflammatory demyelinating polyneuropathy (CIDP), eribulin-related chemotherapy-induced neuropathy, and paraneoplastic neuropathy as the differential diagnoses.
We started intravenous immunoglobulin (IVIG) 400 mg/kg for 5 days, assuming the immune-mediated pathology of her condition. Within two weeks, the ataxia and muscle strength of the distal lower limbs improved, accompanying a decrease in the frequency of myokymia, and the patient started walking more stably. Eribulin was discontinued because of suspicion of association with neuropathy. She was discharged on the 23rd day of admission. During outpatient follow-up, we noted that her gait improved monthly without the need for additional treatments. NCSs performed two months later showed no significant improvement, but neuromuscular echography showed that the limb myokymia had almost disappeared.
Discussion
Eribulin mesylate, an inhibitor of microtubule dynamics, was synthesized with reference to a natural substance called halichondrin B1 extracted from the marine organism halichondria (1). A previous study reported that the incidence of peripheral neuropathy with eribulin treatment was 35%, which was the most common adverse event leading to the discontinuation of eribulin (1). Other microtubule inhibitors, such as vincristine and paclitaxel, also cause neuropathy, the main mechanism of which is axonopathy (5). However, the present case of eribulin-related neuropathy was characterized by 1) multifocal demyelinating neuropathy with conduction block, 2) myokymia, and 3) responsiveness to immunotherapy. To our knowledge, there has only been one other case report on demyelinating neuropathy after the administration of eribulin, wherein the patient presented with multifocal conduction block and myokymia, similar to our case (6). However, that case involved no immunotherapy intervention, or apparent improvement in the symptoms, and the patient ultimately passed away from breast cancer progression within half a year.
Our case of eribulin-related neuropathy showed prominent multifocal demyelination, with NCS findings consistent with MADSAM-type CIDP. MADSAM is characterized by multifocal conduction block in the intermediate nerve trunk, the mechanism of which is speculated to be cell-mediated immunity (7), along with a poorer responsiveness to immunoglobulin and plasmapheresis than typical CIDP (8). Our case was distinguished from MADSAM in that the patient was clearly responsive to immunotherapy and kept improving without additional treatment. Although we did not perform a nerve biopsy, resulting in an insufficient pathological evaluation, the prompt response to IVIG in our case suggested that eribulin administration caused secondary immune-mediated neuropathy involving a mechanism different from MADSAM.
The disappearance of myokymia in the lower extremities after the administration of immunotherapy was another characteristic feature of our case. Limb myokymia has been reported in other demyelinating peripheral nerve disorders, such as Guillain-Barre syndrome (9,10) and CIDP (11,12). MMN also presents fasciculation and myokymia (13) but differs from our case in that it does not show sensory nerve damage. Gerard and Michel reported that conduction blocks lasting more than three months show fasciculation potentials and sometimes even myokymic discharges (14). A few earlier studies mentioned the relationship between axonal hyperpolarization distal to the site of the conduction block and myokymia (15,16). Myokymia disappeared in our patient along with the improvement in other clinical symptoms after the initiation of immunotherapy. Although eribulin-related demyelinating neuropathy is rarely reported, and the detailed mechanism is unclear, the fact that myokymia was a characteristic finding in both the previously reported case (6) and our own suggests that demyelination involving conduction block secondary to eribulin administration may present with unknown pathophysiological conditions related to myokiymia.
In conclusion, it can be inferred from the present case that eribulin can cause demyelinating neuropathy and requires differentiation from other acquired demyelinating neuropathies. If the neuropathy is severe, not only the discontinuation of eribulin but also intervention with immunotherapy may be effective. Further research concerning the detailed mechanism underlying eribulin-induced neuropathy is warranted.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We are grateful to Makoto Samukawa, Susumu Kusunoki (Department of Neurology, Kindai University, Faculty of Medicine), Ryo Yamasaki and Hidenori Ogata (Department of Neurology, Kyusyu University, Faculty of Medicine) for their excellent technical assistance. | Recovering | ReactionOutcome | CC BY-NC-ND | 33678744 | 19,840,712 | 2021-08-15 |
What was the outcome of reaction 'Nerve conduction studies abnormal'? | Eribulin Mesylate-related Multifocal Demyelinating Neuropathy with Myokymia in a Breast Cancer Patient.
We herein report a 48-year-old woman receiving eribulin mesylate for breast cancer who presented with gait disorder, distal limb paresthesia, and weakness progressing monthly. A nerve conduction study indicated demyelination with multifocal conduction block. Considering the immune-mediated pathology of her condition, she was administered intravenous immunoglobulin. Her neurological symptoms improved promptly after intravenous immunoglobulin therapy and eribulin withdrawal. Furthermore, the limb myokymia seen at the time of admission disappeared. Her symptoms continued to improve without additional treatment. We conclude that eribulin was a rare cause of demyelinating neuropathy with multifocal conduction block derived from immune-mediated pathology.
pmcIntroduction
Eribulin mesylate is a microtubule inhibitor used to treat recurrent breast cancer and malignant soft tissue tumors. Neuropathy is reported to be a common side effect of eribulin (1,2). Peripheral neuropathy secondary to microtubule inhibitors usually causes distal limb paresthesia with a characteristic “stocking-glove” distribution, suggesting length-dependent obstacles caused by the disruption of microtubule-dependent transport (3). The main mechanism underlying microtubule inhibitors-related neuropathy has been reported to be axonal injury, and there are no reports of the frequency of demyelination with conduction block (4).
We herein report a woman who experienced reversible demyelinating neuropathy with multifocal conduction block and myokymia that instantly improved on receiving intravenous immunoglobulin and the withdrawal of eribulin, suggesting an immunological mechanism underlying eribulin-related neuropathy.
Case Report
A 48-year-old woman with breast cancer was admitted to our department in May 2020 with a chief complaint of gait disorder. She had been treated with tamoxifen, trastuzumab, pertuzumab, and denosumab for cervical metastasis (C5-6) from May 2018 onwards. Tamoxifen was replaced with eribulin (2 mg per week, for 2 of every 3 weeks) in March 2019 due to the expansion of the primary lesion and increase in tumor markers. In July 2019, she experienced upper limb clumsiness and lower limb paresthesia; subsequently, she noticed gait unsteadiness in December 2019. Since the symptoms were initially thought to be due to compression of the cervical spinal cord, she underwent posterior cervical spinal fusion in January 2020; however, her symptoms worsened despite the surgery. Her gait disorder progressed weekly, and eventually she became unable to walk. She had no medical history other than breast cancer and a family history of neurological disorders.
An examination on admission revealed that the patient had asymmetric limb weakness, especially in the proximal right upper limb and both distal lower limbs, diminished deep tendon reflexes, and paresthesia of the right palm, left first-third fingers, and lower legs. Her vibration sensation of the lower limbs was severely impaired, and she was unable to walk due to ataxia. We also found intermittent myokymic movements on her forearms and lower legs.
Her nerve conduction studies (NCSs) showed decreased conduction velocities and temporal dispersion in all of the motor nerves that were analyzed (Fig. 1). The NCS findings were also characterized by asymmetrical and multifocal conduction block, with most distal amplitudes being normal. An electrodiagnostic inching study on the left median nerve showed conduction block on the proximal forearm (elbow-9 cm). In the F-wave test, A waves were observed on the median, ulnar, and tibial nerves (Fig. 2). The sensory nerve action potential of the median and ulnar nerves also showed temporal dispersion at the same segment as the motor nerves involved (Fig. 3).
Figure 1. The motor nerve conduction study on admission. Temporal dispersion and decreased conduction velocities indicating demyelination were observed. Multifocal asymmetrical conduction block was seen on the forearm and lower leg. B.Elbow: below elbow, A.Elbow: above elbow, Popliteal F.: popliteal fossa
Figure 2. Left median nerve inching test and F wave test. Conduction block was found 9 cm distal to the left elbow. A wave was observed on both the median nerves.
Figure 3. The sensory nerve conduction study on admission. Right median and ulnar nerves showed temporal dispersion at the same segment of the motor nerves involved. B.Elbow: below elbow, A.Elbow: above elbow, SNAP: sensory nerve action potential
The blood tests did not detect monoclonal immunoglobulin, anti-ganglioside antibodies (IgG and IgM for GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, Gal-C and GalNAc-GD1a, IgG for GD1a/GD1b), anti-neurofascin 155 antibody, or anti-contactin-1 antibody. Carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels were within the normal range (<4.9 ng/mL, <26.9 U/mL). The cerebrospinal fluid test showed no increase in protein levels (22 mg/dL) or cell counts (0/μL).
Furthermore, cervical magnetic resonance imaging (MRI) did not suggest progression of the spinal cord compression, and lumber MRI showed no enlargement or contrast enhancement of the lumbar plexus. Needle electromyography showed fasciculation potentials, myokymic discharges, and large polyphasic motor unit potentials on her right abductor pollicis brevis, left quadriceps, and left peroneus longus; however, there were no fibrillation potentials or positive sharp waves at rest. A neuromuscular echogram revealed frequent fasciculation and myokymia on limb muscles, but there was no change in nerve diameter in the area where the conduction block was observed.
We considered multifocal acquired demyelinating sensory and motor (MADSAM)-type chronic inflammatory demyelinating polyneuropathy (CIDP), eribulin-related chemotherapy-induced neuropathy, and paraneoplastic neuropathy as the differential diagnoses.
We started intravenous immunoglobulin (IVIG) 400 mg/kg for 5 days, assuming the immune-mediated pathology of her condition. Within two weeks, the ataxia and muscle strength of the distal lower limbs improved, accompanying a decrease in the frequency of myokymia, and the patient started walking more stably. Eribulin was discontinued because of suspicion of association with neuropathy. She was discharged on the 23rd day of admission. During outpatient follow-up, we noted that her gait improved monthly without the need for additional treatments. NCSs performed two months later showed no significant improvement, but neuromuscular echography showed that the limb myokymia had almost disappeared.
Discussion
Eribulin mesylate, an inhibitor of microtubule dynamics, was synthesized with reference to a natural substance called halichondrin B1 extracted from the marine organism halichondria (1). A previous study reported that the incidence of peripheral neuropathy with eribulin treatment was 35%, which was the most common adverse event leading to the discontinuation of eribulin (1). Other microtubule inhibitors, such as vincristine and paclitaxel, also cause neuropathy, the main mechanism of which is axonopathy (5). However, the present case of eribulin-related neuropathy was characterized by 1) multifocal demyelinating neuropathy with conduction block, 2) myokymia, and 3) responsiveness to immunotherapy. To our knowledge, there has only been one other case report on demyelinating neuropathy after the administration of eribulin, wherein the patient presented with multifocal conduction block and myokymia, similar to our case (6). However, that case involved no immunotherapy intervention, or apparent improvement in the symptoms, and the patient ultimately passed away from breast cancer progression within half a year.
Our case of eribulin-related neuropathy showed prominent multifocal demyelination, with NCS findings consistent with MADSAM-type CIDP. MADSAM is characterized by multifocal conduction block in the intermediate nerve trunk, the mechanism of which is speculated to be cell-mediated immunity (7), along with a poorer responsiveness to immunoglobulin and plasmapheresis than typical CIDP (8). Our case was distinguished from MADSAM in that the patient was clearly responsive to immunotherapy and kept improving without additional treatment. Although we did not perform a nerve biopsy, resulting in an insufficient pathological evaluation, the prompt response to IVIG in our case suggested that eribulin administration caused secondary immune-mediated neuropathy involving a mechanism different from MADSAM.
The disappearance of myokymia in the lower extremities after the administration of immunotherapy was another characteristic feature of our case. Limb myokymia has been reported in other demyelinating peripheral nerve disorders, such as Guillain-Barre syndrome (9,10) and CIDP (11,12). MMN also presents fasciculation and myokymia (13) but differs from our case in that it does not show sensory nerve damage. Gerard and Michel reported that conduction blocks lasting more than three months show fasciculation potentials and sometimes even myokymic discharges (14). A few earlier studies mentioned the relationship between axonal hyperpolarization distal to the site of the conduction block and myokymia (15,16). Myokymia disappeared in our patient along with the improvement in other clinical symptoms after the initiation of immunotherapy. Although eribulin-related demyelinating neuropathy is rarely reported, and the detailed mechanism is unclear, the fact that myokymia was a characteristic finding in both the previously reported case (6) and our own suggests that demyelination involving conduction block secondary to eribulin administration may present with unknown pathophysiological conditions related to myokiymia.
In conclusion, it can be inferred from the present case that eribulin can cause demyelinating neuropathy and requires differentiation from other acquired demyelinating neuropathies. If the neuropathy is severe, not only the discontinuation of eribulin but also intervention with immunotherapy may be effective. Further research concerning the detailed mechanism underlying eribulin-induced neuropathy is warranted.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We are grateful to Makoto Samukawa, Susumu Kusunoki (Department of Neurology, Kindai University, Faculty of Medicine), Ryo Yamasaki and Hidenori Ogata (Department of Neurology, Kyusyu University, Faculty of Medicine) for their excellent technical assistance. | Recovering | ReactionOutcome | CC BY-NC-ND | 33678744 | 19,840,712 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | METHOTREXATE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33678748 | 19,144,983 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | AZATHIOPRINE, METHOTREXATE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33678748 | 19,166,897 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | HUMAN IMMUNOGLOBULIN G, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33678748 | 19,071,211 | 2021-08-15 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33678748 | 19,071,211 | 2021-08-15 |
What was the administration route of drug 'PREDNISOLONE'? | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33678748 | 19,091,993 | 2021-08-15 |
What was the administration route of drug 'TACROLIMUS'? | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33678748 | 19,091,993 | 2021-08-15 |
What was the outcome of reaction 'Condition aggravated'? | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33678748 | 19,144,983 | 2021-08-15 |
What was the outcome of reaction 'Dermatomyositis'? | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33678748 | 19,166,897 | 2021-08-15 |
What was the outcome of reaction 'Panniculitis'? | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33678748 | 19,166,897 | 2021-08-15 |
What was the outcome of reaction 'Rebound effect'? | Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.
Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
pmcIntroduction
Dermatomyositis (DM) is a chronic inflammatory disorder characterized by various cutaneous lesions, along with muscle and lung involvement. Panniculitis is a rare manifestation in patients with DM and reportedly presents as a painful erythematous nodule or plaque (1,2). However, panniculitis without remarkable pain or redness is not well known.
We herein report a patient with panniculitis that appeared as an indurated plaque without pain or redness during clinically amyopathic DM (CADM) treatment, which was successfully treated with methotrexate and azathioprine.
Case Report
A 32-year-old woman was referred to our hospital because of a skin lesion and joint pain. A physical examination revealed periungual erythema, mechanic's hands, mild alopecia, facial erythema, and painful erythema on her right thigh (Fig. 1a, b). There was no muscle weakness or myalgia, and no rales were heard.
Laboratory examinations revealed slight elevations in her levels of creatine kinase (169 U/L; normal, 30-165 U/L), aldolase (8.2 U/L; normal, 2.5-7.5 U/L), serum ferritin (153.0 ng/mL; normal, 10-120 ng/mL), C-reactive protein (0.32 mg/dL; normal, <0.10 mg/dL), and lactate dehydrogenase (327 U/L; normal, 120-230 U/L). The Krebs von den Lungen-6 (369 U/mL; normal, 105-435 U/mL) levels were not elevated. However, a high titer of anti-MDA5 antibody (147.0 index; normal, <32) was observed. Anti-nuclear antibody and other autoantibodies, except for the anti-MDA5 antibody, were negative. Chest computed tomography indicated slight peripheral consolidations (Fig. 1c). A skin biopsy of the right thigh revealed parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis, which was consistent with DM (Fig. 1d). Mucin deposition was not observed, and there was no remarkable change in the fat tissue (Fig. 1e). Given these findings, we established a diagnosis of CADM according to the definition of DM-related terms (3). The patient was treated with prednisolone (60 mg/day) and tacrolimus (3 mg/day), and gradual improvement was observed in the cutaneous lesions and joint pain. Prednisolone was tapered, and she was discharged after one month.
Figure 1. Cutaneous and lung lesions at the first visit. (a) Painful erythema on the right thigh. (b) Periungual erythema and mechanic’s hands. (c) Peripheral consolidations on chest computed tomography (arrows). (d, e) Histopathology of the first biopsy from an erythema on the thigh. (d) Parakeratosis, liquefactive degeneration below the epidermis, and mild lymphoid infiltration in the perivascular area of the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) No remarkable changes in the fat tissue (H&E staining, ×100).
Three months after discharge, however, while still taking 16 mg of prednisolone and 4 mg of tacrolimus daily, the patient noticed an induration on the lateral side of her right thigh, slightly proximal to the initial erythema (Fig. 2a). She did not experience any pain, except when it was strongly compressed. Another small induration also appeared on the left thigh and buttocks, and the firmness and extent of the lesions gradually worsened. Magnetic resonance imaging showed a high-intensity area subcutaneously on fat-suppressed T2-weighted images, which was faintly contrasted (Fig. 2b). A skin biopsy revealed thickening of the epidermis as well as mucin deposition and collagen fiber hyperplasia of the dermis (Fig. 2c, d). Furthermore, fibrosis with mild lymphoid infiltration was observed mostly at the septa of the fat tissue (Fig. 2e). Based on these findings, we established a diagnosis of panniculitis associated with DM. Other cutaneous manifestations, such as periungual erythema and mechanic's hands, were not exacerbated. The patient was treated with an increased dose of prednisolone (40 mg/day) and intravenous immunoglobulin. There was a temporary improvement in the subcutaneous indurations; however, the area and firmness of the lesions worsened when prednisolone was reduced to ≤20 mg/day. Although the additional use of methotrexate was effective, the lesions worsened again when methotrexate was discontinued because of the patient's wish to become pregnant. We added azathioprine, which resulted in evident improvement in the indurations, and reduced the dosage of prednisolone (Fig. 3). The lesions continued to be mildly firm; however, prednisolone was reduced to 5 mg/day with no worsening of the lesions. Peripheral consolidations of the lung were gradually improved throughout the course of treatment.
Figure 2. (a) An indurated plaque without pain on the lateral side of the thigh, slightly proximal to the initial lesion (marker). (b) A high-intensity area noted subcutaneously on fat-suppressed T2-weighted magnetic resonance imaging (arrow). (c-e) Histopathology of the second biopsy from an induration. (c) Interstitial mucin deposition between collagen bundles in the dermis (Alcian Blue-PAS stain, ×100). (d) Thickening of the epidermis and fibrous hyperplasia in the dermis [Hematoxylin and Eosin (H&E) staining, ×200]. (e) Fibrosis and mild lymphoid infiltration in the fat tissue that was not observed at first biopsy (H&E staining, ×100).
Figure 3. Clinical course of the patient. PSL: prednisolone, TAC: tacrolimus, IVIg: intravenous immunoglobulin, MTX: methotrexate, AZA: azathioprine
Discussion
We herein report a patient with panniculitis associated with CADM that developed as an indurated plaque without pain during treatment with prednisolone and tacrolimus. Panniculitis is reported to occur as painful nodules on the buttocks, arms, abdomen, and thighs and rarely manifests in patients with DM (1). Panniculitis can develop at any time during DM, either as an initial symptom or during treatment (4). The histopathologic findings are reportedly similar to those of lupus panniculitis, lobular panniculitis with lymphocytic infiltrate, mucin deposition between collagen bundles, and sclerotic changes in the septa (5,6). In the present case, panniculitis occurred during treatment near the initial erythema but was quite different clinically and histopathologically. It developed silently, without pain or infiltration of lymphocytic cells. The pathogenesis of panniculitis in DM remains unclear; however, the features of our patient may reflect the condition of receiving immunosuppressive treatment with moderate doses of prednisolone and tacrolimus.
Anti-MDA5 antibody is a specific myositis-associated autoantibody, reported to be associated with a high frequency of rapidly progressive interstitial lung disease and joint involvement (7). Regarding cutaneous findings, palmar papules, ulceration, lateral digit hyperkeratosis, and alopecia have been reported as distinctive lesions (8). The titer of anti-MDA5 antibody is reported to correlate with the disease activity in patients with DM (9), and in this case, the titer decreased with improvement in panniculitis and lung lesions. Some reports have discussed the association between panniculitis and MDA5 (10,11); however, the number of patients has been small, and further studies are needed. We found five case reports of patients with anti-MDA5 antibody-positive DM complicated with panniculitis, and all patients had panniculitis as their initial symptom (12-16). Our case showed that patients with anti-MDA5 antibody-positive DM can develop panniculitis even during treatment.
At present, there is no established treatment for panniculitis in DM. High-dose corticosteroids are the main treatment in most cases, and various drugs are used empirically, such as methotrexate (17), hydroxychloroquine (18), and intravenous immunoglobulin (19,20). Our patient developed panniculitis under treatment with prednisolone and tacrolimus. The effectiveness of increasing the dose of prednisolone and intravenous immunoglobulin was temporary, and methotrexate had to be discontinued despite showing a good response because the patient wished to get pregnant. There are limited reports on the effectiveness of azathioprine in DM panniculitis (21); however, azathioprine is reportedly useful, both initially and during maintenance therapy for DM, and contributes to survival benefits. Furthermore, the recommendation of the European League against Rheumatism classified azathioprine as a drug that could be continued during pregnancy and lactation (22). This case showed that azathioprine is a useful option in the treatment of DM panniculitis, especially for women of child-bearing age.
In conclusion, we encountered a patient with DM panniculitis that developed as an indurated plaque without pain during immunosuppressive treatment. The effectiveness of prednisolone, tacrolimus, and intravenous immunoglobulin was insufficient; however, azathioprine showed a good effect of improving the firmness and extent of the lesion. Panniculitis should be suspected when an indurated plaque is observed in patients with DM, even if it is not painful. Similarly, azathioprine may be useful in the treatment of DM panniculitis, including for women of child-bearing age.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33678748 | 19,166,897 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic haematoma'. | Activated Prothrombin Complex Concentrate-Induced Atypical Hemolytic Uremic Syndrome Treated with Eculizumab.
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a set of heterogenous disorders of thrombotic microangiopathy defined by thrombocytopenia, hemolytic anemia, and acute renal failure that is not mediated by shiga toxin. Factor Eight Inhibitor Bypassing Activity (FEIBA) is a concentrate of inactivated and activated coagulation factors that is approved for use to establish hemostasis in patients with hemophilia or acquired factor inhibitors. However, it has recently been used off-label as an anticoagulant reversal therapy among the general population. Additionally, post-market surveillance has shown increased thromboembolic adverse events, whereas micro-thrombotic complications are rarely described. CASE REPORT A 58-year-old man with a history of hypertension and a single deep vein thrombosis on warfarin presented with right upper-quadrant tenderness extending to the right flank. He was found to have a hepatic hematoma and was given activated prothrombin complex concentrate (aPCC) of 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram due to concern for active hemorrhage. Subsequently, he developed anemia, thrombocytopenia, and renal failure consistent with atypical HUS. He was treated with hemodialysis, corticosteroids, plasma exchange, and 4 weekly doses of the anti-C5 antibody eculizumab. The patient subsequently recovered, demonstrating improved hemoglobin, creatinine, and platelets. He eventually achieved hemodialysis independence. Follow-up showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab. CONCLUSIONS Herein, we report the first case of aHUS associated with administration of a single large dose of aPCC for anticoagulation reversal. We postulate a potential mechanism for FEIBA-induced aHUS and report the efficacy of a short trial of eculizumab.
Background
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal impairment [1]. It is generally subdivided into typical or atypical. Shiga toxin-mediated TMA (ST-HUS) is caused by shiga toxin-producing Escherichia coli or Shigella dysenteriae infection, whereas atypical HUS is a heterogenous group of TMA disorders that are both inherited and acquired, caused by complement dysregulation [2]. It has a poor prognosis, with more than half of patients requiring dialysis or experiencing significant renal injury within the first year after diagnosis [3].
Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated prothrombin complex concentrate (aPCC) composed of activated factor VII and inactivated factors II, IX, and X. It is FDA-approved to control bleeding in those with hemophilia A or B with acquired inhibitors or non-hemophiliacs with inhibitors to factors VIII, IX, or XI [4,5]. Recently, data have shown its efficacy in off-label emergent use for anticoagulant reversal therapy [6–9]. Herein, we describe the first reported case of atypical hemolytic uremic syndrome (aHUS) after administration of a large dose of FEIBA.
Case Report
A 58-year-old man taking warfarin for an unprovoked deep vein thrombosis presented with a 1-day history of abdominal and shoulder pain, which progressed to non-radiating right upper-quadrant abdominal pain. His past medical history was significant for hypertension, for which he was taking Lisinopril. He was a 15-pack-year smoker without alcohol or illicit drug use. His family history was significant for a father with liver cancer.
On physical examination, his vitals were stable, he was afebrile, with blood pressure of 130/87 mmHg, heart rate of 67 beats/minute, respiratory rate of 16 breaths/minute, oxygen saturation (SpO2) of >95%, and body mass index of 48 kg/m2. He was in mild distress from pain. His lungs were clear to auscultation and a cardiac examination demonstrated regular rhythm, with no extra heart sounds or murmurs. On abdominal examination, he had mild right upper-quadrant tenderness extending to the right flank. No rashes were found on skin examination. His neurologic exam showed no focal neurological deficits. An initial complete blood count and comprehensive metabolic panel were unremarkable. His INR was therapeutic at 2.8 with platelet count of 259×109/L, creatinine of 1.06 mg/dL, and hemoglobin of 12.9 g/dL. An abdominal ultrasound and subsequent CT abdomen showed a 10-cm-diameter hepatic hematoma suggestive of active bleeding and rupture. Due to concern for potential decompensation, he was given 5 mg of intravenous vitamin K and 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram infused over 1 hour for reversal of therapeutic anticoagulation and establishment of hemostasis. He was transferred to our institution for further management in the Intensive Care Unit.
Within 24 hours of admission, he became oliguric and laboratory studies revealed potassium of 6 mmol/L and creatinine of 5.51 mg/dL (ref 0.84–1.21 mg/dL). Additional laboratory studies showed LDH 2618 IU/L, total bilirubin 0.6 mg/dL, platelet count of 33×109/L, hemoglobin of 8.0 g/dL, reticulocyte count 2.4% (absolute 53.7 cells/mm3), haptoglobin of <30 g/dL, fibrinogen of 445 mg/dL, C3 of 110 mg/dL (ref 96–185 mg/dL), and C4 of 44 mg/dL (ref 18–53 mg/dL). Laboratory trends are shown in Figure 1. A blood smear was significant for schistocytes, spherocytes, and anisocytosis. He was started on hemodialysis for acute renal failure.
Due to presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP), he was begun on plasma exchange and given IV methylprednisolone 1 mg/kg after ADAMTS-13 level was drawn. A stool culture did not grow enterohemorrhagic Escherichia coli (EHEC) strains and antigen PCR was negative for shiga-like toxins 1 and 2. ADAMTS-13 levels returned with 74% activity, showing normal activity (ref >20% activity). Steroids and plasma exchange were discontinued, and he was diagnosed with atypical HUS and given 1 dose 900 mg of intravenous eculizumab per week for a total of 4 weeks. Following administration, his microangiopathic hemolytic anemia improved (Hgb of 8 g/dL), his platelets and LDH corrected toward normal limits (Plts 348×109 and LDH 222 IU/L after 3 weeks of eculizumab), his total bilirubin was 0.3 mg/dL, and his renal function improved (creatinine 2.96 mg/dL after 3 weeks of eculizumab), allowing discontinuation of hemo-dialysis after 2 months. Given the temporal relationship and negative stool cultures, the atypical HUS was deemed to be due to FEIBA administration. Notably, he had no family history of atypical HUS and declined genetic testing due to cost. Hypercoagulable work-up after resolution of the acute event showed heterozygosity for factor V Leiden mutation and was negative for lupus anticoagulant and prothrombin gene mutation and serum levels of protein C and S level within normal limits. Follow-up over 4 years after hospitalization showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab.
Discussion
This is the first report in the literature of an acquired TMA disorder/atypical HUS secondary to administration of the aPCC FEIBA. Use of aPCCs has been gaining favor over component blood products when reversing vitamin K antagonists and direct oral anticoagulants. Several small trials have been conducted that used small doses of 500–1000 units FEIBA infused at 1–2 units per minute to achieve good reversal of vitamin K antagonist [7,8]. This range of fixed doses is much smaller than the therapeutic dose studied in those treated for hemophilia or acquired inhibitors at 50–100 units/kg [5].
Common adverse events of FEIBA include diarrhea, nausea, and vomiting. However, initial studies using FEIBA for hemophiliacs with joint and muscle bleeding [10] or as prophylaxis for bleeding in those with inhibitors [5] did not report thrombotic complications. However, post-marketing surveillance has revealed macro-thrombotic complications (strokes, pulmonary embolisms, and DVTs) in those receiving aPCC, particularly when administered at high doses or increased frequency [4], whereas micro-thrombotic complications are rarely described.
There is a single case report of the prothrombin complex concentrate K-Centra causing atypical HUS. This patient was treated in a similar fashion with HD and eculizumab to achieve a similarly good result [3]. The mechanism of aHUS is hypothesized to occur from impaired regulation of the terminal common complement pathway. Terminal complement activation leads to endothelial damage and development of thrombosis and the 3 features of aHUS: microangiopathic hemolytic anemia, thrombocytopenia, and renal injury [2]. This also explains the efficacy of eculizumab, a monoclonal antibody directed against complement protein C5 [11], in achieving temporary or total remission of atypical HUS in other case reports and in our patient. Thus, the mechanism of FEIBA-induced aHUS may be due to terminal complement activation.
The intricate interplay between the coagulation cascade and complement system is well known; however, the specific physiologic mechanism remains elusive [12]. In vitro assays and in vivo mouse studies have shown the ability of thrombin to activate complement [12,13]. Furthermore, additional ex vivo studies have shown the ability of factors IXa, Xa, XIa, thrombin, and plasmin to cleave C3 and C5 into their activated forms [14,15]. However, more recently, in vivo baboon studies have shown that supraphysiologic levels of factor 10 are able to induce complement activation, but thrombin and plasmin did not activate complement in baboons [16]. Taken together, this demonstrates the potential of coagulation factors to activate terminal complement through both thrombin-dependent and thrombin-independent mechanisms. Herein lies a possible mechanism by which aHUS can be caused by factor administration, as in our patient.
Our patient was treated with a very large dose of FEIBA containing coagulation factors II, VII, IX, and X [17]. Therefore, we hypothesize the supraphysiologic dose of constituent coagulation factors induced terminal complement activation. The resultant terminal complement activation can serve as the impetus for the development of atypical HUS, as illustrated in Figure 2. Unfortunately, we were unable to measure C5 levels during his treatment and further research would be needed to support this mechanism. At the time of this case, our institution did not have ability to measure C5 levels and to track this with treatment. In the setting of emergent anticoagulation reversal therapy with FEIBA in those without hemophilia, this case shows the need to consider conservative dosing to avoid risk of adverse effects.
In addition, debate remains concerning the optimal duration of eculizumab treatment due to its financial burden.
Recommendations based on limited case reports and data suggest that for secondary aHUS caused by drugs, eculizumab may be discontinued when hematologic remission is established [18,19]. In some cases of aHUS, eculizumab has been recommended for indefinite use. However, the scarcity of outcomes data for drug-induced aHUS outside the context of certain drugs like gemcitabine and tacrolimus universal recommendations cannot be made for all drug-induced aHUS [20]. Our case report highlights the efficacy of a limited trial of eculizumab treatment of FEIBA-induced aHUS.
The lack of complete and serial laboratory testing limits our report. Low serum C3 level was observed in a previous case report, while initial complement level was normal in our patient [3]. Low C3 level is not universally observed in the acute phase and the comprehensive complement panel was not available at our institution at the time [21]. Our report also differs by the category of agent used, in that K-Centra contains no activated factors but FEIBA contains activated factor VII. Additionally, work-up for atypical HUS should include genetic testing, but this was not covered by his insurance.
Conclusions
As FEIBA gains further clinical use, this case report will serve as a precaution for the potential development of aHUS as a complication of FEIBA administration. In addition, this case report suggests more conservative dosing of FEIBA in the reversal of vitamin K antagonists in those with no history of hemophilia, as shown in previous small trials. The potential mechanism discussed herein serves as a catalyst for future study and the short trial of eculizumab shows its efficacy in treating aHUS secondary to FEIBA.
Abbreviations
aHUS atypical hemolytic uremic syndrome;
aPCC active prothrombin complex concentrate;
FEIBA factor eight inhibitor bypassing activity;
HD hemodialysis;
TTP thrombotic thrombocytopenic purpura;
PLX plasma exchange
Figure 1. Hemoglobin and platelet count over time by day of admission during hospital course along with temporal relationship of therapeutic interventions (FEIBA, Steroids, Plasma Exchange [PLX], and eculizumab). Each point represents a lab value measurement.
Figure 2. Proposed mechanism of Factor Eight Inhibitor Bypassing Activity (FEIBA)-induced Atypical Hemolytic Uremic Syndrome (aHUS).
Conflicts of Interest
None. | LISINOPRIL, PHYTONADIONE, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33678802 | 19,694,327 | 2021-03-08 |
What was the administration route of drug 'PHYTONADIONE'? | Activated Prothrombin Complex Concentrate-Induced Atypical Hemolytic Uremic Syndrome Treated with Eculizumab.
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a set of heterogenous disorders of thrombotic microangiopathy defined by thrombocytopenia, hemolytic anemia, and acute renal failure that is not mediated by shiga toxin. Factor Eight Inhibitor Bypassing Activity (FEIBA) is a concentrate of inactivated and activated coagulation factors that is approved for use to establish hemostasis in patients with hemophilia or acquired factor inhibitors. However, it has recently been used off-label as an anticoagulant reversal therapy among the general population. Additionally, post-market surveillance has shown increased thromboembolic adverse events, whereas micro-thrombotic complications are rarely described. CASE REPORT A 58-year-old man with a history of hypertension and a single deep vein thrombosis on warfarin presented with right upper-quadrant tenderness extending to the right flank. He was found to have a hepatic hematoma and was given activated prothrombin complex concentrate (aPCC) of 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram due to concern for active hemorrhage. Subsequently, he developed anemia, thrombocytopenia, and renal failure consistent with atypical HUS. He was treated with hemodialysis, corticosteroids, plasma exchange, and 4 weekly doses of the anti-C5 antibody eculizumab. The patient subsequently recovered, demonstrating improved hemoglobin, creatinine, and platelets. He eventually achieved hemodialysis independence. Follow-up showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab. CONCLUSIONS Herein, we report the first case of aHUS associated with administration of a single large dose of aPCC for anticoagulation reversal. We postulate a potential mechanism for FEIBA-induced aHUS and report the efficacy of a short trial of eculizumab.
Background
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal impairment [1]. It is generally subdivided into typical or atypical. Shiga toxin-mediated TMA (ST-HUS) is caused by shiga toxin-producing Escherichia coli or Shigella dysenteriae infection, whereas atypical HUS is a heterogenous group of TMA disorders that are both inherited and acquired, caused by complement dysregulation [2]. It has a poor prognosis, with more than half of patients requiring dialysis or experiencing significant renal injury within the first year after diagnosis [3].
Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated prothrombin complex concentrate (aPCC) composed of activated factor VII and inactivated factors II, IX, and X. It is FDA-approved to control bleeding in those with hemophilia A or B with acquired inhibitors or non-hemophiliacs with inhibitors to factors VIII, IX, or XI [4,5]. Recently, data have shown its efficacy in off-label emergent use for anticoagulant reversal therapy [6–9]. Herein, we describe the first reported case of atypical hemolytic uremic syndrome (aHUS) after administration of a large dose of FEIBA.
Case Report
A 58-year-old man taking warfarin for an unprovoked deep vein thrombosis presented with a 1-day history of abdominal and shoulder pain, which progressed to non-radiating right upper-quadrant abdominal pain. His past medical history was significant for hypertension, for which he was taking Lisinopril. He was a 15-pack-year smoker without alcohol or illicit drug use. His family history was significant for a father with liver cancer.
On physical examination, his vitals were stable, he was afebrile, with blood pressure of 130/87 mmHg, heart rate of 67 beats/minute, respiratory rate of 16 breaths/minute, oxygen saturation (SpO2) of >95%, and body mass index of 48 kg/m2. He was in mild distress from pain. His lungs were clear to auscultation and a cardiac examination demonstrated regular rhythm, with no extra heart sounds or murmurs. On abdominal examination, he had mild right upper-quadrant tenderness extending to the right flank. No rashes were found on skin examination. His neurologic exam showed no focal neurological deficits. An initial complete blood count and comprehensive metabolic panel were unremarkable. His INR was therapeutic at 2.8 with platelet count of 259×109/L, creatinine of 1.06 mg/dL, and hemoglobin of 12.9 g/dL. An abdominal ultrasound and subsequent CT abdomen showed a 10-cm-diameter hepatic hematoma suggestive of active bleeding and rupture. Due to concern for potential decompensation, he was given 5 mg of intravenous vitamin K and 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram infused over 1 hour for reversal of therapeutic anticoagulation and establishment of hemostasis. He was transferred to our institution for further management in the Intensive Care Unit.
Within 24 hours of admission, he became oliguric and laboratory studies revealed potassium of 6 mmol/L and creatinine of 5.51 mg/dL (ref 0.84–1.21 mg/dL). Additional laboratory studies showed LDH 2618 IU/L, total bilirubin 0.6 mg/dL, platelet count of 33×109/L, hemoglobin of 8.0 g/dL, reticulocyte count 2.4% (absolute 53.7 cells/mm3), haptoglobin of <30 g/dL, fibrinogen of 445 mg/dL, C3 of 110 mg/dL (ref 96–185 mg/dL), and C4 of 44 mg/dL (ref 18–53 mg/dL). Laboratory trends are shown in Figure 1. A blood smear was significant for schistocytes, spherocytes, and anisocytosis. He was started on hemodialysis for acute renal failure.
Due to presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP), he was begun on plasma exchange and given IV methylprednisolone 1 mg/kg after ADAMTS-13 level was drawn. A stool culture did not grow enterohemorrhagic Escherichia coli (EHEC) strains and antigen PCR was negative for shiga-like toxins 1 and 2. ADAMTS-13 levels returned with 74% activity, showing normal activity (ref >20% activity). Steroids and plasma exchange were discontinued, and he was diagnosed with atypical HUS and given 1 dose 900 mg of intravenous eculizumab per week for a total of 4 weeks. Following administration, his microangiopathic hemolytic anemia improved (Hgb of 8 g/dL), his platelets and LDH corrected toward normal limits (Plts 348×109 and LDH 222 IU/L after 3 weeks of eculizumab), his total bilirubin was 0.3 mg/dL, and his renal function improved (creatinine 2.96 mg/dL after 3 weeks of eculizumab), allowing discontinuation of hemo-dialysis after 2 months. Given the temporal relationship and negative stool cultures, the atypical HUS was deemed to be due to FEIBA administration. Notably, he had no family history of atypical HUS and declined genetic testing due to cost. Hypercoagulable work-up after resolution of the acute event showed heterozygosity for factor V Leiden mutation and was negative for lupus anticoagulant and prothrombin gene mutation and serum levels of protein C and S level within normal limits. Follow-up over 4 years after hospitalization showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab.
Discussion
This is the first report in the literature of an acquired TMA disorder/atypical HUS secondary to administration of the aPCC FEIBA. Use of aPCCs has been gaining favor over component blood products when reversing vitamin K antagonists and direct oral anticoagulants. Several small trials have been conducted that used small doses of 500–1000 units FEIBA infused at 1–2 units per minute to achieve good reversal of vitamin K antagonist [7,8]. This range of fixed doses is much smaller than the therapeutic dose studied in those treated for hemophilia or acquired inhibitors at 50–100 units/kg [5].
Common adverse events of FEIBA include diarrhea, nausea, and vomiting. However, initial studies using FEIBA for hemophiliacs with joint and muscle bleeding [10] or as prophylaxis for bleeding in those with inhibitors [5] did not report thrombotic complications. However, post-marketing surveillance has revealed macro-thrombotic complications (strokes, pulmonary embolisms, and DVTs) in those receiving aPCC, particularly when administered at high doses or increased frequency [4], whereas micro-thrombotic complications are rarely described.
There is a single case report of the prothrombin complex concentrate K-Centra causing atypical HUS. This patient was treated in a similar fashion with HD and eculizumab to achieve a similarly good result [3]. The mechanism of aHUS is hypothesized to occur from impaired regulation of the terminal common complement pathway. Terminal complement activation leads to endothelial damage and development of thrombosis and the 3 features of aHUS: microangiopathic hemolytic anemia, thrombocytopenia, and renal injury [2]. This also explains the efficacy of eculizumab, a monoclonal antibody directed against complement protein C5 [11], in achieving temporary or total remission of atypical HUS in other case reports and in our patient. Thus, the mechanism of FEIBA-induced aHUS may be due to terminal complement activation.
The intricate interplay between the coagulation cascade and complement system is well known; however, the specific physiologic mechanism remains elusive [12]. In vitro assays and in vivo mouse studies have shown the ability of thrombin to activate complement [12,13]. Furthermore, additional ex vivo studies have shown the ability of factors IXa, Xa, XIa, thrombin, and plasmin to cleave C3 and C5 into their activated forms [14,15]. However, more recently, in vivo baboon studies have shown that supraphysiologic levels of factor 10 are able to induce complement activation, but thrombin and plasmin did not activate complement in baboons [16]. Taken together, this demonstrates the potential of coagulation factors to activate terminal complement through both thrombin-dependent and thrombin-independent mechanisms. Herein lies a possible mechanism by which aHUS can be caused by factor administration, as in our patient.
Our patient was treated with a very large dose of FEIBA containing coagulation factors II, VII, IX, and X [17]. Therefore, we hypothesize the supraphysiologic dose of constituent coagulation factors induced terminal complement activation. The resultant terminal complement activation can serve as the impetus for the development of atypical HUS, as illustrated in Figure 2. Unfortunately, we were unable to measure C5 levels during his treatment and further research would be needed to support this mechanism. At the time of this case, our institution did not have ability to measure C5 levels and to track this with treatment. In the setting of emergent anticoagulation reversal therapy with FEIBA in those without hemophilia, this case shows the need to consider conservative dosing to avoid risk of adverse effects.
In addition, debate remains concerning the optimal duration of eculizumab treatment due to its financial burden.
Recommendations based on limited case reports and data suggest that for secondary aHUS caused by drugs, eculizumab may be discontinued when hematologic remission is established [18,19]. In some cases of aHUS, eculizumab has been recommended for indefinite use. However, the scarcity of outcomes data for drug-induced aHUS outside the context of certain drugs like gemcitabine and tacrolimus universal recommendations cannot be made for all drug-induced aHUS [20]. Our case report highlights the efficacy of a limited trial of eculizumab treatment of FEIBA-induced aHUS.
The lack of complete and serial laboratory testing limits our report. Low serum C3 level was observed in a previous case report, while initial complement level was normal in our patient [3]. Low C3 level is not universally observed in the acute phase and the comprehensive complement panel was not available at our institution at the time [21]. Our report also differs by the category of agent used, in that K-Centra contains no activated factors but FEIBA contains activated factor VII. Additionally, work-up for atypical HUS should include genetic testing, but this was not covered by his insurance.
Conclusions
As FEIBA gains further clinical use, this case report will serve as a precaution for the potential development of aHUS as a complication of FEIBA administration. In addition, this case report suggests more conservative dosing of FEIBA in the reversal of vitamin K antagonists in those with no history of hemophilia, as shown in previous small trials. The potential mechanism discussed herein serves as a catalyst for future study and the short trial of eculizumab shows its efficacy in treating aHUS secondary to FEIBA.
Abbreviations
aHUS atypical hemolytic uremic syndrome;
aPCC active prothrombin complex concentrate;
FEIBA factor eight inhibitor bypassing activity;
HD hemodialysis;
TTP thrombotic thrombocytopenic purpura;
PLX plasma exchange
Figure 1. Hemoglobin and platelet count over time by day of admission during hospital course along with temporal relationship of therapeutic interventions (FEIBA, Steroids, Plasma Exchange [PLX], and eculizumab). Each point represents a lab value measurement.
Figure 2. Proposed mechanism of Factor Eight Inhibitor Bypassing Activity (FEIBA)-induced Atypical Hemolytic Uremic Syndrome (aHUS).
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33678802 | 19,694,327 | 2021-03-08 |
What was the dosage of drug 'COAGULATION FACTOR IX HUMAN\COAGULATION FACTOR VII HUMAN\COAGULATION FACTOR X HUMAN\PROTHROMBIN'? | Activated Prothrombin Complex Concentrate-Induced Atypical Hemolytic Uremic Syndrome Treated with Eculizumab.
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a set of heterogenous disorders of thrombotic microangiopathy defined by thrombocytopenia, hemolytic anemia, and acute renal failure that is not mediated by shiga toxin. Factor Eight Inhibitor Bypassing Activity (FEIBA) is a concentrate of inactivated and activated coagulation factors that is approved for use to establish hemostasis in patients with hemophilia or acquired factor inhibitors. However, it has recently been used off-label as an anticoagulant reversal therapy among the general population. Additionally, post-market surveillance has shown increased thromboembolic adverse events, whereas micro-thrombotic complications are rarely described. CASE REPORT A 58-year-old man with a history of hypertension and a single deep vein thrombosis on warfarin presented with right upper-quadrant tenderness extending to the right flank. He was found to have a hepatic hematoma and was given activated prothrombin complex concentrate (aPCC) of 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram due to concern for active hemorrhage. Subsequently, he developed anemia, thrombocytopenia, and renal failure consistent with atypical HUS. He was treated with hemodialysis, corticosteroids, plasma exchange, and 4 weekly doses of the anti-C5 antibody eculizumab. The patient subsequently recovered, demonstrating improved hemoglobin, creatinine, and platelets. He eventually achieved hemodialysis independence. Follow-up showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab. CONCLUSIONS Herein, we report the first case of aHUS associated with administration of a single large dose of aPCC for anticoagulation reversal. We postulate a potential mechanism for FEIBA-induced aHUS and report the efficacy of a short trial of eculizumab.
Background
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal impairment [1]. It is generally subdivided into typical or atypical. Shiga toxin-mediated TMA (ST-HUS) is caused by shiga toxin-producing Escherichia coli or Shigella dysenteriae infection, whereas atypical HUS is a heterogenous group of TMA disorders that are both inherited and acquired, caused by complement dysregulation [2]. It has a poor prognosis, with more than half of patients requiring dialysis or experiencing significant renal injury within the first year after diagnosis [3].
Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated prothrombin complex concentrate (aPCC) composed of activated factor VII and inactivated factors II, IX, and X. It is FDA-approved to control bleeding in those with hemophilia A or B with acquired inhibitors or non-hemophiliacs with inhibitors to factors VIII, IX, or XI [4,5]. Recently, data have shown its efficacy in off-label emergent use for anticoagulant reversal therapy [6–9]. Herein, we describe the first reported case of atypical hemolytic uremic syndrome (aHUS) after administration of a large dose of FEIBA.
Case Report
A 58-year-old man taking warfarin for an unprovoked deep vein thrombosis presented with a 1-day history of abdominal and shoulder pain, which progressed to non-radiating right upper-quadrant abdominal pain. His past medical history was significant for hypertension, for which he was taking Lisinopril. He was a 15-pack-year smoker without alcohol or illicit drug use. His family history was significant for a father with liver cancer.
On physical examination, his vitals were stable, he was afebrile, with blood pressure of 130/87 mmHg, heart rate of 67 beats/minute, respiratory rate of 16 breaths/minute, oxygen saturation (SpO2) of >95%, and body mass index of 48 kg/m2. He was in mild distress from pain. His lungs were clear to auscultation and a cardiac examination demonstrated regular rhythm, with no extra heart sounds or murmurs. On abdominal examination, he had mild right upper-quadrant tenderness extending to the right flank. No rashes were found on skin examination. His neurologic exam showed no focal neurological deficits. An initial complete blood count and comprehensive metabolic panel were unremarkable. His INR was therapeutic at 2.8 with platelet count of 259×109/L, creatinine of 1.06 mg/dL, and hemoglobin of 12.9 g/dL. An abdominal ultrasound and subsequent CT abdomen showed a 10-cm-diameter hepatic hematoma suggestive of active bleeding and rupture. Due to concern for potential decompensation, he was given 5 mg of intravenous vitamin K and 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram infused over 1 hour for reversal of therapeutic anticoagulation and establishment of hemostasis. He was transferred to our institution for further management in the Intensive Care Unit.
Within 24 hours of admission, he became oliguric and laboratory studies revealed potassium of 6 mmol/L and creatinine of 5.51 mg/dL (ref 0.84–1.21 mg/dL). Additional laboratory studies showed LDH 2618 IU/L, total bilirubin 0.6 mg/dL, platelet count of 33×109/L, hemoglobin of 8.0 g/dL, reticulocyte count 2.4% (absolute 53.7 cells/mm3), haptoglobin of <30 g/dL, fibrinogen of 445 mg/dL, C3 of 110 mg/dL (ref 96–185 mg/dL), and C4 of 44 mg/dL (ref 18–53 mg/dL). Laboratory trends are shown in Figure 1. A blood smear was significant for schistocytes, spherocytes, and anisocytosis. He was started on hemodialysis for acute renal failure.
Due to presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP), he was begun on plasma exchange and given IV methylprednisolone 1 mg/kg after ADAMTS-13 level was drawn. A stool culture did not grow enterohemorrhagic Escherichia coli (EHEC) strains and antigen PCR was negative for shiga-like toxins 1 and 2. ADAMTS-13 levels returned with 74% activity, showing normal activity (ref >20% activity). Steroids and plasma exchange were discontinued, and he was diagnosed with atypical HUS and given 1 dose 900 mg of intravenous eculizumab per week for a total of 4 weeks. Following administration, his microangiopathic hemolytic anemia improved (Hgb of 8 g/dL), his platelets and LDH corrected toward normal limits (Plts 348×109 and LDH 222 IU/L after 3 weeks of eculizumab), his total bilirubin was 0.3 mg/dL, and his renal function improved (creatinine 2.96 mg/dL after 3 weeks of eculizumab), allowing discontinuation of hemo-dialysis after 2 months. Given the temporal relationship and negative stool cultures, the atypical HUS was deemed to be due to FEIBA administration. Notably, he had no family history of atypical HUS and declined genetic testing due to cost. Hypercoagulable work-up after resolution of the acute event showed heterozygosity for factor V Leiden mutation and was negative for lupus anticoagulant and prothrombin gene mutation and serum levels of protein C and S level within normal limits. Follow-up over 4 years after hospitalization showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab.
Discussion
This is the first report in the literature of an acquired TMA disorder/atypical HUS secondary to administration of the aPCC FEIBA. Use of aPCCs has been gaining favor over component blood products when reversing vitamin K antagonists and direct oral anticoagulants. Several small trials have been conducted that used small doses of 500–1000 units FEIBA infused at 1–2 units per minute to achieve good reversal of vitamin K antagonist [7,8]. This range of fixed doses is much smaller than the therapeutic dose studied in those treated for hemophilia or acquired inhibitors at 50–100 units/kg [5].
Common adverse events of FEIBA include diarrhea, nausea, and vomiting. However, initial studies using FEIBA for hemophiliacs with joint and muscle bleeding [10] or as prophylaxis for bleeding in those with inhibitors [5] did not report thrombotic complications. However, post-marketing surveillance has revealed macro-thrombotic complications (strokes, pulmonary embolisms, and DVTs) in those receiving aPCC, particularly when administered at high doses or increased frequency [4], whereas micro-thrombotic complications are rarely described.
There is a single case report of the prothrombin complex concentrate K-Centra causing atypical HUS. This patient was treated in a similar fashion with HD and eculizumab to achieve a similarly good result [3]. The mechanism of aHUS is hypothesized to occur from impaired regulation of the terminal common complement pathway. Terminal complement activation leads to endothelial damage and development of thrombosis and the 3 features of aHUS: microangiopathic hemolytic anemia, thrombocytopenia, and renal injury [2]. This also explains the efficacy of eculizumab, a monoclonal antibody directed against complement protein C5 [11], in achieving temporary or total remission of atypical HUS in other case reports and in our patient. Thus, the mechanism of FEIBA-induced aHUS may be due to terminal complement activation.
The intricate interplay between the coagulation cascade and complement system is well known; however, the specific physiologic mechanism remains elusive [12]. In vitro assays and in vivo mouse studies have shown the ability of thrombin to activate complement [12,13]. Furthermore, additional ex vivo studies have shown the ability of factors IXa, Xa, XIa, thrombin, and plasmin to cleave C3 and C5 into their activated forms [14,15]. However, more recently, in vivo baboon studies have shown that supraphysiologic levels of factor 10 are able to induce complement activation, but thrombin and plasmin did not activate complement in baboons [16]. Taken together, this demonstrates the potential of coagulation factors to activate terminal complement through both thrombin-dependent and thrombin-independent mechanisms. Herein lies a possible mechanism by which aHUS can be caused by factor administration, as in our patient.
Our patient was treated with a very large dose of FEIBA containing coagulation factors II, VII, IX, and X [17]. Therefore, we hypothesize the supraphysiologic dose of constituent coagulation factors induced terminal complement activation. The resultant terminal complement activation can serve as the impetus for the development of atypical HUS, as illustrated in Figure 2. Unfortunately, we were unable to measure C5 levels during his treatment and further research would be needed to support this mechanism. At the time of this case, our institution did not have ability to measure C5 levels and to track this with treatment. In the setting of emergent anticoagulation reversal therapy with FEIBA in those without hemophilia, this case shows the need to consider conservative dosing to avoid risk of adverse effects.
In addition, debate remains concerning the optimal duration of eculizumab treatment due to its financial burden.
Recommendations based on limited case reports and data suggest that for secondary aHUS caused by drugs, eculizumab may be discontinued when hematologic remission is established [18,19]. In some cases of aHUS, eculizumab has been recommended for indefinite use. However, the scarcity of outcomes data for drug-induced aHUS outside the context of certain drugs like gemcitabine and tacrolimus universal recommendations cannot be made for all drug-induced aHUS [20]. Our case report highlights the efficacy of a limited trial of eculizumab treatment of FEIBA-induced aHUS.
The lack of complete and serial laboratory testing limits our report. Low serum C3 level was observed in a previous case report, while initial complement level was normal in our patient [3]. Low C3 level is not universally observed in the acute phase and the comprehensive complement panel was not available at our institution at the time [21]. Our report also differs by the category of agent used, in that K-Centra contains no activated factors but FEIBA contains activated factor VII. Additionally, work-up for atypical HUS should include genetic testing, but this was not covered by his insurance.
Conclusions
As FEIBA gains further clinical use, this case report will serve as a precaution for the potential development of aHUS as a complication of FEIBA administration. In addition, this case report suggests more conservative dosing of FEIBA in the reversal of vitamin K antagonists in those with no history of hemophilia, as shown in previous small trials. The potential mechanism discussed herein serves as a catalyst for future study and the short trial of eculizumab shows its efficacy in treating aHUS secondary to FEIBA.
Abbreviations
aHUS atypical hemolytic uremic syndrome;
aPCC active prothrombin complex concentrate;
FEIBA factor eight inhibitor bypassing activity;
HD hemodialysis;
TTP thrombotic thrombocytopenic purpura;
PLX plasma exchange
Figure 1. Hemoglobin and platelet count over time by day of admission during hospital course along with temporal relationship of therapeutic interventions (FEIBA, Steroids, Plasma Exchange [PLX], and eculizumab). Each point represents a lab value measurement.
Figure 2. Proposed mechanism of Factor Eight Inhibitor Bypassing Activity (FEIBA)-induced Atypical Hemolytic Uremic Syndrome (aHUS).
Conflicts of Interest
None. | 100 INTERNATIONAL UNIT/KILOGRAM | DrugDosageText | CC BY-NC-ND | 33678802 | 19,047,900 | 2021-03-08 |
What was the dosage of drug 'PHYTONADIONE'? | Activated Prothrombin Complex Concentrate-Induced Atypical Hemolytic Uremic Syndrome Treated with Eculizumab.
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a set of heterogenous disorders of thrombotic microangiopathy defined by thrombocytopenia, hemolytic anemia, and acute renal failure that is not mediated by shiga toxin. Factor Eight Inhibitor Bypassing Activity (FEIBA) is a concentrate of inactivated and activated coagulation factors that is approved for use to establish hemostasis in patients with hemophilia or acquired factor inhibitors. However, it has recently been used off-label as an anticoagulant reversal therapy among the general population. Additionally, post-market surveillance has shown increased thromboembolic adverse events, whereas micro-thrombotic complications are rarely described. CASE REPORT A 58-year-old man with a history of hypertension and a single deep vein thrombosis on warfarin presented with right upper-quadrant tenderness extending to the right flank. He was found to have a hepatic hematoma and was given activated prothrombin complex concentrate (aPCC) of 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram due to concern for active hemorrhage. Subsequently, he developed anemia, thrombocytopenia, and renal failure consistent with atypical HUS. He was treated with hemodialysis, corticosteroids, plasma exchange, and 4 weekly doses of the anti-C5 antibody eculizumab. The patient subsequently recovered, demonstrating improved hemoglobin, creatinine, and platelets. He eventually achieved hemodialysis independence. Follow-up showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab. CONCLUSIONS Herein, we report the first case of aHUS associated with administration of a single large dose of aPCC for anticoagulation reversal. We postulate a potential mechanism for FEIBA-induced aHUS and report the efficacy of a short trial of eculizumab.
Background
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal impairment [1]. It is generally subdivided into typical or atypical. Shiga toxin-mediated TMA (ST-HUS) is caused by shiga toxin-producing Escherichia coli or Shigella dysenteriae infection, whereas atypical HUS is a heterogenous group of TMA disorders that are both inherited and acquired, caused by complement dysregulation [2]. It has a poor prognosis, with more than half of patients requiring dialysis or experiencing significant renal injury within the first year after diagnosis [3].
Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated prothrombin complex concentrate (aPCC) composed of activated factor VII and inactivated factors II, IX, and X. It is FDA-approved to control bleeding in those with hemophilia A or B with acquired inhibitors or non-hemophiliacs with inhibitors to factors VIII, IX, or XI [4,5]. Recently, data have shown its efficacy in off-label emergent use for anticoagulant reversal therapy [6–9]. Herein, we describe the first reported case of atypical hemolytic uremic syndrome (aHUS) after administration of a large dose of FEIBA.
Case Report
A 58-year-old man taking warfarin for an unprovoked deep vein thrombosis presented with a 1-day history of abdominal and shoulder pain, which progressed to non-radiating right upper-quadrant abdominal pain. His past medical history was significant for hypertension, for which he was taking Lisinopril. He was a 15-pack-year smoker without alcohol or illicit drug use. His family history was significant for a father with liver cancer.
On physical examination, his vitals were stable, he was afebrile, with blood pressure of 130/87 mmHg, heart rate of 67 beats/minute, respiratory rate of 16 breaths/minute, oxygen saturation (SpO2) of >95%, and body mass index of 48 kg/m2. He was in mild distress from pain. His lungs were clear to auscultation and a cardiac examination demonstrated regular rhythm, with no extra heart sounds or murmurs. On abdominal examination, he had mild right upper-quadrant tenderness extending to the right flank. No rashes were found on skin examination. His neurologic exam showed no focal neurological deficits. An initial complete blood count and comprehensive metabolic panel were unremarkable. His INR was therapeutic at 2.8 with platelet count of 259×109/L, creatinine of 1.06 mg/dL, and hemoglobin of 12.9 g/dL. An abdominal ultrasound and subsequent CT abdomen showed a 10-cm-diameter hepatic hematoma suggestive of active bleeding and rupture. Due to concern for potential decompensation, he was given 5 mg of intravenous vitamin K and 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram infused over 1 hour for reversal of therapeutic anticoagulation and establishment of hemostasis. He was transferred to our institution for further management in the Intensive Care Unit.
Within 24 hours of admission, he became oliguric and laboratory studies revealed potassium of 6 mmol/L and creatinine of 5.51 mg/dL (ref 0.84–1.21 mg/dL). Additional laboratory studies showed LDH 2618 IU/L, total bilirubin 0.6 mg/dL, platelet count of 33×109/L, hemoglobin of 8.0 g/dL, reticulocyte count 2.4% (absolute 53.7 cells/mm3), haptoglobin of <30 g/dL, fibrinogen of 445 mg/dL, C3 of 110 mg/dL (ref 96–185 mg/dL), and C4 of 44 mg/dL (ref 18–53 mg/dL). Laboratory trends are shown in Figure 1. A blood smear was significant for schistocytes, spherocytes, and anisocytosis. He was started on hemodialysis for acute renal failure.
Due to presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP), he was begun on plasma exchange and given IV methylprednisolone 1 mg/kg after ADAMTS-13 level was drawn. A stool culture did not grow enterohemorrhagic Escherichia coli (EHEC) strains and antigen PCR was negative for shiga-like toxins 1 and 2. ADAMTS-13 levels returned with 74% activity, showing normal activity (ref >20% activity). Steroids and plasma exchange were discontinued, and he was diagnosed with atypical HUS and given 1 dose 900 mg of intravenous eculizumab per week for a total of 4 weeks. Following administration, his microangiopathic hemolytic anemia improved (Hgb of 8 g/dL), his platelets and LDH corrected toward normal limits (Plts 348×109 and LDH 222 IU/L after 3 weeks of eculizumab), his total bilirubin was 0.3 mg/dL, and his renal function improved (creatinine 2.96 mg/dL after 3 weeks of eculizumab), allowing discontinuation of hemo-dialysis after 2 months. Given the temporal relationship and negative stool cultures, the atypical HUS was deemed to be due to FEIBA administration. Notably, he had no family history of atypical HUS and declined genetic testing due to cost. Hypercoagulable work-up after resolution of the acute event showed heterozygosity for factor V Leiden mutation and was negative for lupus anticoagulant and prothrombin gene mutation and serum levels of protein C and S level within normal limits. Follow-up over 4 years after hospitalization showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab.
Discussion
This is the first report in the literature of an acquired TMA disorder/atypical HUS secondary to administration of the aPCC FEIBA. Use of aPCCs has been gaining favor over component blood products when reversing vitamin K antagonists and direct oral anticoagulants. Several small trials have been conducted that used small doses of 500–1000 units FEIBA infused at 1–2 units per minute to achieve good reversal of vitamin K antagonist [7,8]. This range of fixed doses is much smaller than the therapeutic dose studied in those treated for hemophilia or acquired inhibitors at 50–100 units/kg [5].
Common adverse events of FEIBA include diarrhea, nausea, and vomiting. However, initial studies using FEIBA for hemophiliacs with joint and muscle bleeding [10] or as prophylaxis for bleeding in those with inhibitors [5] did not report thrombotic complications. However, post-marketing surveillance has revealed macro-thrombotic complications (strokes, pulmonary embolisms, and DVTs) in those receiving aPCC, particularly when administered at high doses or increased frequency [4], whereas micro-thrombotic complications are rarely described.
There is a single case report of the prothrombin complex concentrate K-Centra causing atypical HUS. This patient was treated in a similar fashion with HD and eculizumab to achieve a similarly good result [3]. The mechanism of aHUS is hypothesized to occur from impaired regulation of the terminal common complement pathway. Terminal complement activation leads to endothelial damage and development of thrombosis and the 3 features of aHUS: microangiopathic hemolytic anemia, thrombocytopenia, and renal injury [2]. This also explains the efficacy of eculizumab, a monoclonal antibody directed against complement protein C5 [11], in achieving temporary or total remission of atypical HUS in other case reports and in our patient. Thus, the mechanism of FEIBA-induced aHUS may be due to terminal complement activation.
The intricate interplay between the coagulation cascade and complement system is well known; however, the specific physiologic mechanism remains elusive [12]. In vitro assays and in vivo mouse studies have shown the ability of thrombin to activate complement [12,13]. Furthermore, additional ex vivo studies have shown the ability of factors IXa, Xa, XIa, thrombin, and plasmin to cleave C3 and C5 into their activated forms [14,15]. However, more recently, in vivo baboon studies have shown that supraphysiologic levels of factor 10 are able to induce complement activation, but thrombin and plasmin did not activate complement in baboons [16]. Taken together, this demonstrates the potential of coagulation factors to activate terminal complement through both thrombin-dependent and thrombin-independent mechanisms. Herein lies a possible mechanism by which aHUS can be caused by factor administration, as in our patient.
Our patient was treated with a very large dose of FEIBA containing coagulation factors II, VII, IX, and X [17]. Therefore, we hypothesize the supraphysiologic dose of constituent coagulation factors induced terminal complement activation. The resultant terminal complement activation can serve as the impetus for the development of atypical HUS, as illustrated in Figure 2. Unfortunately, we were unable to measure C5 levels during his treatment and further research would be needed to support this mechanism. At the time of this case, our institution did not have ability to measure C5 levels and to track this with treatment. In the setting of emergent anticoagulation reversal therapy with FEIBA in those without hemophilia, this case shows the need to consider conservative dosing to avoid risk of adverse effects.
In addition, debate remains concerning the optimal duration of eculizumab treatment due to its financial burden.
Recommendations based on limited case reports and data suggest that for secondary aHUS caused by drugs, eculizumab may be discontinued when hematologic remission is established [18,19]. In some cases of aHUS, eculizumab has been recommended for indefinite use. However, the scarcity of outcomes data for drug-induced aHUS outside the context of certain drugs like gemcitabine and tacrolimus universal recommendations cannot be made for all drug-induced aHUS [20]. Our case report highlights the efficacy of a limited trial of eculizumab treatment of FEIBA-induced aHUS.
The lack of complete and serial laboratory testing limits our report. Low serum C3 level was observed in a previous case report, while initial complement level was normal in our patient [3]. Low C3 level is not universally observed in the acute phase and the comprehensive complement panel was not available at our institution at the time [21]. Our report also differs by the category of agent used, in that K-Centra contains no activated factors but FEIBA contains activated factor VII. Additionally, work-up for atypical HUS should include genetic testing, but this was not covered by his insurance.
Conclusions
As FEIBA gains further clinical use, this case report will serve as a precaution for the potential development of aHUS as a complication of FEIBA administration. In addition, this case report suggests more conservative dosing of FEIBA in the reversal of vitamin K antagonists in those with no history of hemophilia, as shown in previous small trials. The potential mechanism discussed herein serves as a catalyst for future study and the short trial of eculizumab shows its efficacy in treating aHUS secondary to FEIBA.
Abbreviations
aHUS atypical hemolytic uremic syndrome;
aPCC active prothrombin complex concentrate;
FEIBA factor eight inhibitor bypassing activity;
HD hemodialysis;
TTP thrombotic thrombocytopenic purpura;
PLX plasma exchange
Figure 1. Hemoglobin and platelet count over time by day of admission during hospital course along with temporal relationship of therapeutic interventions (FEIBA, Steroids, Plasma Exchange [PLX], and eculizumab). Each point represents a lab value measurement.
Figure 2. Proposed mechanism of Factor Eight Inhibitor Bypassing Activity (FEIBA)-induced Atypical Hemolytic Uremic Syndrome (aHUS).
Conflicts of Interest
None. | 5 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33678802 | 19,694,327 | 2021-03-08 |
What was the outcome of reaction 'Atypical haemolytic uraemic syndrome'? | Activated Prothrombin Complex Concentrate-Induced Atypical Hemolytic Uremic Syndrome Treated with Eculizumab.
BACKGROUND Atypical hemolytic uremic syndrome (aHUS) is a set of heterogenous disorders of thrombotic microangiopathy defined by thrombocytopenia, hemolytic anemia, and acute renal failure that is not mediated by shiga toxin. Factor Eight Inhibitor Bypassing Activity (FEIBA) is a concentrate of inactivated and activated coagulation factors that is approved for use to establish hemostasis in patients with hemophilia or acquired factor inhibitors. However, it has recently been used off-label as an anticoagulant reversal therapy among the general population. Additionally, post-market surveillance has shown increased thromboembolic adverse events, whereas micro-thrombotic complications are rarely described. CASE REPORT A 58-year-old man with a history of hypertension and a single deep vein thrombosis on warfarin presented with right upper-quadrant tenderness extending to the right flank. He was found to have a hepatic hematoma and was given activated prothrombin complex concentrate (aPCC) of 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram due to concern for active hemorrhage. Subsequently, he developed anemia, thrombocytopenia, and renal failure consistent with atypical HUS. He was treated with hemodialysis, corticosteroids, plasma exchange, and 4 weekly doses of the anti-C5 antibody eculizumab. The patient subsequently recovered, demonstrating improved hemoglobin, creatinine, and platelets. He eventually achieved hemodialysis independence. Follow-up showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab. CONCLUSIONS Herein, we report the first case of aHUS associated with administration of a single large dose of aPCC for anticoagulation reversal. We postulate a potential mechanism for FEIBA-induced aHUS and report the efficacy of a short trial of eculizumab.
Background
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal impairment [1]. It is generally subdivided into typical or atypical. Shiga toxin-mediated TMA (ST-HUS) is caused by shiga toxin-producing Escherichia coli or Shigella dysenteriae infection, whereas atypical HUS is a heterogenous group of TMA disorders that are both inherited and acquired, caused by complement dysregulation [2]. It has a poor prognosis, with more than half of patients requiring dialysis or experiencing significant renal injury within the first year after diagnosis [3].
Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated prothrombin complex concentrate (aPCC) composed of activated factor VII and inactivated factors II, IX, and X. It is FDA-approved to control bleeding in those with hemophilia A or B with acquired inhibitors or non-hemophiliacs with inhibitors to factors VIII, IX, or XI [4,5]. Recently, data have shown its efficacy in off-label emergent use for anticoagulant reversal therapy [6–9]. Herein, we describe the first reported case of atypical hemolytic uremic syndrome (aHUS) after administration of a large dose of FEIBA.
Case Report
A 58-year-old man taking warfarin for an unprovoked deep vein thrombosis presented with a 1-day history of abdominal and shoulder pain, which progressed to non-radiating right upper-quadrant abdominal pain. His past medical history was significant for hypertension, for which he was taking Lisinopril. He was a 15-pack-year smoker without alcohol or illicit drug use. His family history was significant for a father with liver cancer.
On physical examination, his vitals were stable, he was afebrile, with blood pressure of 130/87 mmHg, heart rate of 67 beats/minute, respiratory rate of 16 breaths/minute, oxygen saturation (SpO2) of >95%, and body mass index of 48 kg/m2. He was in mild distress from pain. His lungs were clear to auscultation and a cardiac examination demonstrated regular rhythm, with no extra heart sounds or murmurs. On abdominal examination, he had mild right upper-quadrant tenderness extending to the right flank. No rashes were found on skin examination. His neurologic exam showed no focal neurological deficits. An initial complete blood count and comprehensive metabolic panel were unremarkable. His INR was therapeutic at 2.8 with platelet count of 259×109/L, creatinine of 1.06 mg/dL, and hemoglobin of 12.9 g/dL. An abdominal ultrasound and subsequent CT abdomen showed a 10-cm-diameter hepatic hematoma suggestive of active bleeding and rupture. Due to concern for potential decompensation, he was given 5 mg of intravenous vitamin K and 14 150 units of anti-inhibitor coagulant complex at 100 units per kilogram infused over 1 hour for reversal of therapeutic anticoagulation and establishment of hemostasis. He was transferred to our institution for further management in the Intensive Care Unit.
Within 24 hours of admission, he became oliguric and laboratory studies revealed potassium of 6 mmol/L and creatinine of 5.51 mg/dL (ref 0.84–1.21 mg/dL). Additional laboratory studies showed LDH 2618 IU/L, total bilirubin 0.6 mg/dL, platelet count of 33×109/L, hemoglobin of 8.0 g/dL, reticulocyte count 2.4% (absolute 53.7 cells/mm3), haptoglobin of <30 g/dL, fibrinogen of 445 mg/dL, C3 of 110 mg/dL (ref 96–185 mg/dL), and C4 of 44 mg/dL (ref 18–53 mg/dL). Laboratory trends are shown in Figure 1. A blood smear was significant for schistocytes, spherocytes, and anisocytosis. He was started on hemodialysis for acute renal failure.
Due to presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP), he was begun on plasma exchange and given IV methylprednisolone 1 mg/kg after ADAMTS-13 level was drawn. A stool culture did not grow enterohemorrhagic Escherichia coli (EHEC) strains and antigen PCR was negative for shiga-like toxins 1 and 2. ADAMTS-13 levels returned with 74% activity, showing normal activity (ref >20% activity). Steroids and plasma exchange were discontinued, and he was diagnosed with atypical HUS and given 1 dose 900 mg of intravenous eculizumab per week for a total of 4 weeks. Following administration, his microangiopathic hemolytic anemia improved (Hgb of 8 g/dL), his platelets and LDH corrected toward normal limits (Plts 348×109 and LDH 222 IU/L after 3 weeks of eculizumab), his total bilirubin was 0.3 mg/dL, and his renal function improved (creatinine 2.96 mg/dL after 3 weeks of eculizumab), allowing discontinuation of hemo-dialysis after 2 months. Given the temporal relationship and negative stool cultures, the atypical HUS was deemed to be due to FEIBA administration. Notably, he had no family history of atypical HUS and declined genetic testing due to cost. Hypercoagulable work-up after resolution of the acute event showed heterozygosity for factor V Leiden mutation and was negative for lupus anticoagulant and prothrombin gene mutation and serum levels of protein C and S level within normal limits. Follow-up over 4 years after hospitalization showed no evidence of recurrent atypical HUS and the patient has not needed maintenance eculizumab.
Discussion
This is the first report in the literature of an acquired TMA disorder/atypical HUS secondary to administration of the aPCC FEIBA. Use of aPCCs has been gaining favor over component blood products when reversing vitamin K antagonists and direct oral anticoagulants. Several small trials have been conducted that used small doses of 500–1000 units FEIBA infused at 1–2 units per minute to achieve good reversal of vitamin K antagonist [7,8]. This range of fixed doses is much smaller than the therapeutic dose studied in those treated for hemophilia or acquired inhibitors at 50–100 units/kg [5].
Common adverse events of FEIBA include diarrhea, nausea, and vomiting. However, initial studies using FEIBA for hemophiliacs with joint and muscle bleeding [10] or as prophylaxis for bleeding in those with inhibitors [5] did not report thrombotic complications. However, post-marketing surveillance has revealed macro-thrombotic complications (strokes, pulmonary embolisms, and DVTs) in those receiving aPCC, particularly when administered at high doses or increased frequency [4], whereas micro-thrombotic complications are rarely described.
There is a single case report of the prothrombin complex concentrate K-Centra causing atypical HUS. This patient was treated in a similar fashion with HD and eculizumab to achieve a similarly good result [3]. The mechanism of aHUS is hypothesized to occur from impaired regulation of the terminal common complement pathway. Terminal complement activation leads to endothelial damage and development of thrombosis and the 3 features of aHUS: microangiopathic hemolytic anemia, thrombocytopenia, and renal injury [2]. This also explains the efficacy of eculizumab, a monoclonal antibody directed against complement protein C5 [11], in achieving temporary or total remission of atypical HUS in other case reports and in our patient. Thus, the mechanism of FEIBA-induced aHUS may be due to terminal complement activation.
The intricate interplay between the coagulation cascade and complement system is well known; however, the specific physiologic mechanism remains elusive [12]. In vitro assays and in vivo mouse studies have shown the ability of thrombin to activate complement [12,13]. Furthermore, additional ex vivo studies have shown the ability of factors IXa, Xa, XIa, thrombin, and plasmin to cleave C3 and C5 into their activated forms [14,15]. However, more recently, in vivo baboon studies have shown that supraphysiologic levels of factor 10 are able to induce complement activation, but thrombin and plasmin did not activate complement in baboons [16]. Taken together, this demonstrates the potential of coagulation factors to activate terminal complement through both thrombin-dependent and thrombin-independent mechanisms. Herein lies a possible mechanism by which aHUS can be caused by factor administration, as in our patient.
Our patient was treated with a very large dose of FEIBA containing coagulation factors II, VII, IX, and X [17]. Therefore, we hypothesize the supraphysiologic dose of constituent coagulation factors induced terminal complement activation. The resultant terminal complement activation can serve as the impetus for the development of atypical HUS, as illustrated in Figure 2. Unfortunately, we were unable to measure C5 levels during his treatment and further research would be needed to support this mechanism. At the time of this case, our institution did not have ability to measure C5 levels and to track this with treatment. In the setting of emergent anticoagulation reversal therapy with FEIBA in those without hemophilia, this case shows the need to consider conservative dosing to avoid risk of adverse effects.
In addition, debate remains concerning the optimal duration of eculizumab treatment due to its financial burden.
Recommendations based on limited case reports and data suggest that for secondary aHUS caused by drugs, eculizumab may be discontinued when hematologic remission is established [18,19]. In some cases of aHUS, eculizumab has been recommended for indefinite use. However, the scarcity of outcomes data for drug-induced aHUS outside the context of certain drugs like gemcitabine and tacrolimus universal recommendations cannot be made for all drug-induced aHUS [20]. Our case report highlights the efficacy of a limited trial of eculizumab treatment of FEIBA-induced aHUS.
The lack of complete and serial laboratory testing limits our report. Low serum C3 level was observed in a previous case report, while initial complement level was normal in our patient [3]. Low C3 level is not universally observed in the acute phase and the comprehensive complement panel was not available at our institution at the time [21]. Our report also differs by the category of agent used, in that K-Centra contains no activated factors but FEIBA contains activated factor VII. Additionally, work-up for atypical HUS should include genetic testing, but this was not covered by his insurance.
Conclusions
As FEIBA gains further clinical use, this case report will serve as a precaution for the potential development of aHUS as a complication of FEIBA administration. In addition, this case report suggests more conservative dosing of FEIBA in the reversal of vitamin K antagonists in those with no history of hemophilia, as shown in previous small trials. The potential mechanism discussed herein serves as a catalyst for future study and the short trial of eculizumab shows its efficacy in treating aHUS secondary to FEIBA.
Abbreviations
aHUS atypical hemolytic uremic syndrome;
aPCC active prothrombin complex concentrate;
FEIBA factor eight inhibitor bypassing activity;
HD hemodialysis;
TTP thrombotic thrombocytopenic purpura;
PLX plasma exchange
Figure 1. Hemoglobin and platelet count over time by day of admission during hospital course along with temporal relationship of therapeutic interventions (FEIBA, Steroids, Plasma Exchange [PLX], and eculizumab). Each point represents a lab value measurement.
Figure 2. Proposed mechanism of Factor Eight Inhibitor Bypassing Activity (FEIBA)-induced Atypical Hemolytic Uremic Syndrome (aHUS).
Conflicts of Interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33678802 | 19,061,907 | 2021-03-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular tachycardia'. | Overdrive suppression of postoperative sustained ventricular tachycardia by atrial pacing and its hemodynamic effect.
Sustained ventricular tachycardia (VT) in the early postoperative period following intracardiac repair for tetralogy of Fallot is rare. In stable VT, amiodarone forms the mainstay of management. However, where amiodarone and other antiarrhythmic drugs are contraindicated, suppressive overdrive atrial pacing can be used as a safe and efficient alternative to maintain cardiac output. We present a case of 1-year 5-month-old child who developed VT with low cardiac output syndrome with deranged hepatic function, who was managed efficiently using suppressive atrial pacing to ameliorate the effects of sustained VT.
INTRODUCTION
Arrhythmia is a common phenomenon in the early postoperative period following congenital heart surgeries (CHSs), and its management sometimes imposes a great challenge. Right ventriculotomy and muscle resection during tetralogy of Fallot (TOF) repair predispose to arrhythmias – most commonly being junctional ectopic tachycardia. However, ventricular tachycardia (VT) is rare. Usually, amiodarone is the best available therapeutic option besides various general measures to control any form of arrhythmias. Although overdrive pacing is well established in atrial arrhythmias, its application in ventricular arrhythmias (VAs) is not well explored, especially in CHS. Patients where established pharmacotherapy is not feasible, suppressive overdrive atrial pacing is a safe and effective alternative.
CASE REPORT
A 1-year 5-month-old cyanosed female child with a diagnosis of TOF underwent intracardiac repair with transannular patch. The child had high left atrial pressure (LAP) while coming off cardiopulmonary bypass, and hence, sternum was stented electively followed by delayed sternal closure on the postoperative day (POD) 1. Postextubation, the child was reintubated on POD5 following tachypnea with poor gas exchange. ECHO imaging revealed severe right ventricular (RV) diastolic dysfunction, leading to congestive hepatopathy. The high LAP also added onto the insult. Serum bilirubin was 8.2 mg%, and serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were 2840 and 2120 U/L, respectively. She was on inotropic supports of adrenaline, noradrenaline, and milrinone infusion of 0.05 miC/kg/min.
Frequent nonsustained VT developed on the POD6. The possible correctable causes were evaluated for and arrhythmogenic nature of the inotropes being concluded as the cause, were replaced with levosimendan infusion. Transient initial success was achieved with intermittent boluses of MgSO4 and xylocaine injection. With progression, the VT became more frequent and resistant to medical therapy. Amiodarone could not be used in view of deranged liver function, and options of using beta-blocker and calcium channel blockers were ruled out in view of persistent ventricular dysfunction. A 12-lead electrocardiogram showed peaked, nonnotched, tall QRS in the inferior leads with qS in the lead aVL characteristically seen with ventricular premature complexes (VPCs), arising from anterosuperior portion of septal aspect of RV outflow [Figure 1].
Figure 1 A 12-lead electrocardiogram showing the morphology of QRS complex of ventricular bigeminy (qS in aVL)
On POD7, rhythm worsened to ventricular bigeminy degenerating to sustained monomorphic stable VT with borderline hemodynamics [Figure 2]. Atrial electrogram performed during tachycardia showed VA dissociation. Overdrive atrial pacing was established at 160 bpm above the rate of VT with intraoperatively placed epicardial leads [Figure 3]. Cardiac output improved with atrial pacing with disappearance of VT. This beneficial effect was only observed when paced at a rate higher than VT along with the added advantage of the atrial kick.
Figure 2 Varying rhythms with ventricular bigeminy, short VT runs, and sustained VT. VT: Ventricular tachycardia
Figure 3 Atrial overdrive pacing suppressing VT. VT: Ventricular tachycardia
Within hours, rhythm reverted to ventricular bigeminy followed by infrequent ventricular ectopics. Pacing was readjusted to 140 bpm to maintain optimal hemodynamics. The child reverted to normal sinus rhythm with the improvement of cardiac function in the following 24 h.
DISCUSSION
Overdrive pacing has been well documented to revert rhythm in re-entrant arrhythmia in adults.[1] VA, though rare in the early postoperative period, are deleterious to the recovering myocardium.[2] The patient's QRS morphology clearly favored VPC's as wide QRS was not preceded byPwaves and PP interval continued unaltered. We presumed that this arrhythmia had a nonre-entrant mechanism with either an automaticity or triggered activity. The location of outflow, induction with isoprenaline infusion, and the fixed coupling interval of VPCs favors triggered activity as the most common mechanism of idiopathic RVOT ectopics which might have been provoked by the adrenergic state.
Normally, sustained VT with rates <150 bpm is well tolerated in the postoperative period in the absence of ventricular dysfunction. At higher rates, opposing effect is observed as diastolic filling time is affected. Patients with hypertrophied ventricles having diastolic dysfunctions responds poorly to the loss of AV synchrony and results in low cardiac output even with a lower ventricular rate. Moreover, RV output remains fixed in RV dysfunction.
Overdrive pacing with desirable effect is limited to VT between 140 and 170 bpm because AV node should conduct with desirable hemodynamic changes. The patient's rate <150 bpm with effective 1:1 AV conduction with regular QRS intervals was sufficient enough to overdrive.
Although ventricular overdrive pacing is an established management modality of VT, it can result in interventricular dys-synchrony, hypotension, and at times degeneration of arrhythmia to ventricular fibrillation. On the contrary, atrial pacing results in better synchronous ventricular contraction due to narrow QRS. This emphasizes the need for epicardial atrial leads, especially in such cases or cases where VA is expected such as ASO and ALCAPA repair.
The decision to treat an arrhythmia should be based on hemodynamic necessity and not just for reverting rhythm to normal. Amiodarone is a drug of choice in cases of hemodynamically stable VT.[3]
CONCLUSION
Suppressive atrial overdrive pacing can be used alone or as a hybrid to pharmacotherapy to control VT in the early postoperative period. However, this beneficial effect of overdrive atrial pacing losses its advantage at higher rates. Further studies with varied subsets of diagnosis are required to incorporate this beneficial effect as a management modality for VT.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | EPINEPHRINE, MILRINONE, NOREPINEPHRINE | DrugsGivenReaction | CC BY-NC-SA | 33679069 | 20,041,968 | 2021 |
What was the dosage of drug 'MILRINONE'? | Overdrive suppression of postoperative sustained ventricular tachycardia by atrial pacing and its hemodynamic effect.
Sustained ventricular tachycardia (VT) in the early postoperative period following intracardiac repair for tetralogy of Fallot is rare. In stable VT, amiodarone forms the mainstay of management. However, where amiodarone and other antiarrhythmic drugs are contraindicated, suppressive overdrive atrial pacing can be used as a safe and efficient alternative to maintain cardiac output. We present a case of 1-year 5-month-old child who developed VT with low cardiac output syndrome with deranged hepatic function, who was managed efficiently using suppressive atrial pacing to ameliorate the effects of sustained VT.
INTRODUCTION
Arrhythmia is a common phenomenon in the early postoperative period following congenital heart surgeries (CHSs), and its management sometimes imposes a great challenge. Right ventriculotomy and muscle resection during tetralogy of Fallot (TOF) repair predispose to arrhythmias – most commonly being junctional ectopic tachycardia. However, ventricular tachycardia (VT) is rare. Usually, amiodarone is the best available therapeutic option besides various general measures to control any form of arrhythmias. Although overdrive pacing is well established in atrial arrhythmias, its application in ventricular arrhythmias (VAs) is not well explored, especially in CHS. Patients where established pharmacotherapy is not feasible, suppressive overdrive atrial pacing is a safe and effective alternative.
CASE REPORT
A 1-year 5-month-old cyanosed female child with a diagnosis of TOF underwent intracardiac repair with transannular patch. The child had high left atrial pressure (LAP) while coming off cardiopulmonary bypass, and hence, sternum was stented electively followed by delayed sternal closure on the postoperative day (POD) 1. Postextubation, the child was reintubated on POD5 following tachypnea with poor gas exchange. ECHO imaging revealed severe right ventricular (RV) diastolic dysfunction, leading to congestive hepatopathy. The high LAP also added onto the insult. Serum bilirubin was 8.2 mg%, and serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were 2840 and 2120 U/L, respectively. She was on inotropic supports of adrenaline, noradrenaline, and milrinone infusion of 0.05 miC/kg/min.
Frequent nonsustained VT developed on the POD6. The possible correctable causes were evaluated for and arrhythmogenic nature of the inotropes being concluded as the cause, were replaced with levosimendan infusion. Transient initial success was achieved with intermittent boluses of MgSO4 and xylocaine injection. With progression, the VT became more frequent and resistant to medical therapy. Amiodarone could not be used in view of deranged liver function, and options of using beta-blocker and calcium channel blockers were ruled out in view of persistent ventricular dysfunction. A 12-lead electrocardiogram showed peaked, nonnotched, tall QRS in the inferior leads with qS in the lead aVL characteristically seen with ventricular premature complexes (VPCs), arising from anterosuperior portion of septal aspect of RV outflow [Figure 1].
Figure 1 A 12-lead electrocardiogram showing the morphology of QRS complex of ventricular bigeminy (qS in aVL)
On POD7, rhythm worsened to ventricular bigeminy degenerating to sustained monomorphic stable VT with borderline hemodynamics [Figure 2]. Atrial electrogram performed during tachycardia showed VA dissociation. Overdrive atrial pacing was established at 160 bpm above the rate of VT with intraoperatively placed epicardial leads [Figure 3]. Cardiac output improved with atrial pacing with disappearance of VT. This beneficial effect was only observed when paced at a rate higher than VT along with the added advantage of the atrial kick.
Figure 2 Varying rhythms with ventricular bigeminy, short VT runs, and sustained VT. VT: Ventricular tachycardia
Figure 3 Atrial overdrive pacing suppressing VT. VT: Ventricular tachycardia
Within hours, rhythm reverted to ventricular bigeminy followed by infrequent ventricular ectopics. Pacing was readjusted to 140 bpm to maintain optimal hemodynamics. The child reverted to normal sinus rhythm with the improvement of cardiac function in the following 24 h.
DISCUSSION
Overdrive pacing has been well documented to revert rhythm in re-entrant arrhythmia in adults.[1] VA, though rare in the early postoperative period, are deleterious to the recovering myocardium.[2] The patient's QRS morphology clearly favored VPC's as wide QRS was not preceded byPwaves and PP interval continued unaltered. We presumed that this arrhythmia had a nonre-entrant mechanism with either an automaticity or triggered activity. The location of outflow, induction with isoprenaline infusion, and the fixed coupling interval of VPCs favors triggered activity as the most common mechanism of idiopathic RVOT ectopics which might have been provoked by the adrenergic state.
Normally, sustained VT with rates <150 bpm is well tolerated in the postoperative period in the absence of ventricular dysfunction. At higher rates, opposing effect is observed as diastolic filling time is affected. Patients with hypertrophied ventricles having diastolic dysfunctions responds poorly to the loss of AV synchrony and results in low cardiac output even with a lower ventricular rate. Moreover, RV output remains fixed in RV dysfunction.
Overdrive pacing with desirable effect is limited to VT between 140 and 170 bpm because AV node should conduct with desirable hemodynamic changes. The patient's rate <150 bpm with effective 1:1 AV conduction with regular QRS intervals was sufficient enough to overdrive.
Although ventricular overdrive pacing is an established management modality of VT, it can result in interventricular dys-synchrony, hypotension, and at times degeneration of arrhythmia to ventricular fibrillation. On the contrary, atrial pacing results in better synchronous ventricular contraction due to narrow QRS. This emphasizes the need for epicardial atrial leads, especially in such cases or cases where VA is expected such as ASO and ALCAPA repair.
The decision to treat an arrhythmia should be based on hemodynamic necessity and not just for reverting rhythm to normal. Amiodarone is a drug of choice in cases of hemodynamically stable VT.[3]
CONCLUSION
Suppressive atrial overdrive pacing can be used alone or as a hybrid to pharmacotherapy to control VT in the early postoperative period. However, this beneficial effect of overdrive atrial pacing losses its advantage at higher rates. Further studies with varied subsets of diagnosis are required to incorporate this beneficial effect as a management modality for VT.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | UNK (0.05 MIC/KG/MIN) | DrugDosageText | CC BY-NC-SA | 33679069 | 20,041,968 | 2021 |
What was the outcome of reaction 'Ventricular tachycardia'? | Overdrive suppression of postoperative sustained ventricular tachycardia by atrial pacing and its hemodynamic effect.
Sustained ventricular tachycardia (VT) in the early postoperative period following intracardiac repair for tetralogy of Fallot is rare. In stable VT, amiodarone forms the mainstay of management. However, where amiodarone and other antiarrhythmic drugs are contraindicated, suppressive overdrive atrial pacing can be used as a safe and efficient alternative to maintain cardiac output. We present a case of 1-year 5-month-old child who developed VT with low cardiac output syndrome with deranged hepatic function, who was managed efficiently using suppressive atrial pacing to ameliorate the effects of sustained VT.
INTRODUCTION
Arrhythmia is a common phenomenon in the early postoperative period following congenital heart surgeries (CHSs), and its management sometimes imposes a great challenge. Right ventriculotomy and muscle resection during tetralogy of Fallot (TOF) repair predispose to arrhythmias – most commonly being junctional ectopic tachycardia. However, ventricular tachycardia (VT) is rare. Usually, amiodarone is the best available therapeutic option besides various general measures to control any form of arrhythmias. Although overdrive pacing is well established in atrial arrhythmias, its application in ventricular arrhythmias (VAs) is not well explored, especially in CHS. Patients where established pharmacotherapy is not feasible, suppressive overdrive atrial pacing is a safe and effective alternative.
CASE REPORT
A 1-year 5-month-old cyanosed female child with a diagnosis of TOF underwent intracardiac repair with transannular patch. The child had high left atrial pressure (LAP) while coming off cardiopulmonary bypass, and hence, sternum was stented electively followed by delayed sternal closure on the postoperative day (POD) 1. Postextubation, the child was reintubated on POD5 following tachypnea with poor gas exchange. ECHO imaging revealed severe right ventricular (RV) diastolic dysfunction, leading to congestive hepatopathy. The high LAP also added onto the insult. Serum bilirubin was 8.2 mg%, and serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were 2840 and 2120 U/L, respectively. She was on inotropic supports of adrenaline, noradrenaline, and milrinone infusion of 0.05 miC/kg/min.
Frequent nonsustained VT developed on the POD6. The possible correctable causes were evaluated for and arrhythmogenic nature of the inotropes being concluded as the cause, were replaced with levosimendan infusion. Transient initial success was achieved with intermittent boluses of MgSO4 and xylocaine injection. With progression, the VT became more frequent and resistant to medical therapy. Amiodarone could not be used in view of deranged liver function, and options of using beta-blocker and calcium channel blockers were ruled out in view of persistent ventricular dysfunction. A 12-lead electrocardiogram showed peaked, nonnotched, tall QRS in the inferior leads with qS in the lead aVL characteristically seen with ventricular premature complexes (VPCs), arising from anterosuperior portion of septal aspect of RV outflow [Figure 1].
Figure 1 A 12-lead electrocardiogram showing the morphology of QRS complex of ventricular bigeminy (qS in aVL)
On POD7, rhythm worsened to ventricular bigeminy degenerating to sustained monomorphic stable VT with borderline hemodynamics [Figure 2]. Atrial electrogram performed during tachycardia showed VA dissociation. Overdrive atrial pacing was established at 160 bpm above the rate of VT with intraoperatively placed epicardial leads [Figure 3]. Cardiac output improved with atrial pacing with disappearance of VT. This beneficial effect was only observed when paced at a rate higher than VT along with the added advantage of the atrial kick.
Figure 2 Varying rhythms with ventricular bigeminy, short VT runs, and sustained VT. VT: Ventricular tachycardia
Figure 3 Atrial overdrive pacing suppressing VT. VT: Ventricular tachycardia
Within hours, rhythm reverted to ventricular bigeminy followed by infrequent ventricular ectopics. Pacing was readjusted to 140 bpm to maintain optimal hemodynamics. The child reverted to normal sinus rhythm with the improvement of cardiac function in the following 24 h.
DISCUSSION
Overdrive pacing has been well documented to revert rhythm in re-entrant arrhythmia in adults.[1] VA, though rare in the early postoperative period, are deleterious to the recovering myocardium.[2] The patient's QRS morphology clearly favored VPC's as wide QRS was not preceded byPwaves and PP interval continued unaltered. We presumed that this arrhythmia had a nonre-entrant mechanism with either an automaticity or triggered activity. The location of outflow, induction with isoprenaline infusion, and the fixed coupling interval of VPCs favors triggered activity as the most common mechanism of idiopathic RVOT ectopics which might have been provoked by the adrenergic state.
Normally, sustained VT with rates <150 bpm is well tolerated in the postoperative period in the absence of ventricular dysfunction. At higher rates, opposing effect is observed as diastolic filling time is affected. Patients with hypertrophied ventricles having diastolic dysfunctions responds poorly to the loss of AV synchrony and results in low cardiac output even with a lower ventricular rate. Moreover, RV output remains fixed in RV dysfunction.
Overdrive pacing with desirable effect is limited to VT between 140 and 170 bpm because AV node should conduct with desirable hemodynamic changes. The patient's rate <150 bpm with effective 1:1 AV conduction with regular QRS intervals was sufficient enough to overdrive.
Although ventricular overdrive pacing is an established management modality of VT, it can result in interventricular dys-synchrony, hypotension, and at times degeneration of arrhythmia to ventricular fibrillation. On the contrary, atrial pacing results in better synchronous ventricular contraction due to narrow QRS. This emphasizes the need for epicardial atrial leads, especially in such cases or cases where VA is expected such as ASO and ALCAPA repair.
The decision to treat an arrhythmia should be based on hemodynamic necessity and not just for reverting rhythm to normal. Amiodarone is a drug of choice in cases of hemodynamically stable VT.[3]
CONCLUSION
Suppressive atrial overdrive pacing can be used alone or as a hybrid to pharmacotherapy to control VT in the early postoperative period. However, this beneficial effect of overdrive atrial pacing losses its advantage at higher rates. Further studies with varied subsets of diagnosis are required to incorporate this beneficial effect as a management modality for VT.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | Recovering | ReactionOutcome | CC BY-NC-SA | 33679069 | 20,041,968 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypogammaglobulinaemia'. | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB | DrugsGivenReaction | CC BY | 33679772 | 19,286,872 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB | DrugsGivenReaction | CC BY | 33679772 | 19,286,872 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | HYDROXYCHLOROQUINE, MYCOPHENOLATE MOFETIL, PREDNISONE, RITUXIMAB | DrugsGivenReaction | CC BY | 33679772 | 19,286,872 | 2021 |
What was the administration route of drug 'PREDNISONE'? | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Oral | DrugAdministrationRoute | CC BY | 33679772 | 19,286,872 | 2021 |
What was the dosage of drug 'HYDROXYCHLOROQUINE'? | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | UNKNOWN | DrugDosageText | CC BY | 33679772 | 19,286,872 | 2021 |
What was the dosage of drug 'PREDNISONE'? | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | UNKNOWN | DrugDosageText | CC BY | 33679772 | 19,286,872 | 2021 |
What was the outcome of reaction 'Neutropenia'? | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33679772 | 19,286,872 | 2021 |
What was the outcome of reaction 'Pyrexia'? | Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype.
Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.
Introduction
The gene TNFAIP3 (tumor necrosis factor alpha-induced protein 3) encodes the protein A20, an essential negative regulator of NF-κB-mediated inflammation (1, 2). A20 is a potent inhibitor of NF-κB signaling in response to TNF-α, numerous other pro-inflammatory cytokines, and innate immune receptor activation via its ubiquitin-editing domains (3, 4). Heterozygous loss-of-function mutations in A20 causes haploinsufficiency of A20 (HA20) and a Behcet’s-like disease in children (prominent mucosal ulcers and intestinal symptoms) (5), and have been associated with a number of other autoimmune and autoinflammatory diseases (5–8) as well as lymphomas and other cancers (7). We present a case of a child with a novel TNFAIP3 mutation causing HA20, with clinical features resembling systemic lupus erythematosus with associated recurrent lymphadenopathy and progressive hypogammaglobulinemia.
Case Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up, and Outcomes
During the patient’s first year of life, she was diagnosed with atopic dermatitis (controlled non-pharmacologically) and had a documented history of viral upper respiratory illness, bacterial acute otitis media, pneumonia, and one hospitalization for sepsis and respiratory symptoms.
At 2.5 years of age, the patient presented with persistent posterior cervical lymphadenopathy, which was monitored and eventually surgically resected at the age of 3; the pathologic findings were non-specific. She returned several times between the ages of 5–7 years for posterior cervical lymphadenopathy and fever of unknown origin in the absence of other symptoms. When she was 7.5 years old, she was hospitalized for concern of meningitis with evolving symptoms of prolonged fevers, headache, and neck pain. Cerebrospinal fluid (CSF) studies were notable for elevated white blood cells (WBCs; 0.8 x 109 cells/L), but tests for infectious diseases including Gram stain, bacterial culture, tick-borne pathogen screening, tuberculosis, and viral testing were all negative. During this hospitalization, she became pancytopenic requiring transfusion (WBC nadir of 3.1 x 109 cells/L, and thrombocytopenia to 30 x 109 cells/L); a bone marrow biopsy demonstrated normal cellularity and no pathologic changes. Repeat biopsy of a right posterior cervical lymph node showed features consistent with atypical lymphoid hyperplasia but not a lymphoproliferative disorder. Rheumatology was consulted during this hospitalization for persistent fevers, emergence of a maculopapular rash, and concern for macrophage activation syndrome. Notable laboratory values at that time included an elevated anti-nuclear antibody (ANA of 12.4, normal <1.0) and anti-double-stranded DNA antibodies (dsDNA of 167, normal <29 IU/ml), negative anti-extractable nuclear antigen (ENA) antibodies (negative SS-A/Ro, SS-B/La, scleroderma, Smith, and ribonucleoprotein antibodies), negative cardiolipin antibodies and negative lupus anticoagulant, positive anti-platelet antibodies (Gp2b3a), normal complement C3 and C4 levels, elevated ferritin (peak of 2300 ng/mL), normal triglycerides, and moderate elevation of creatine kinase (CK) and transaminases. Serum immunoglobulin levels were normal to elevated (IgG 1530, normal 500–1,400 mg/dl; IgA 360, normal 47–249 mg/dl; IgM 188, normal 47–252 mg/dl; IgE 535, normal 0–150 kIU/L); serum protein electrophoresis revealed polyclonal gammopathy. Rheumatology continued to follow this patient in clinic after hospitalization due to a suspicion of an evolving inflammatory illness with intermittent fevers of unclear etiology. Autoimmune lymphoproliferative syndrome (ALPS) was considered, though CD4/CD8 double-negative T-cell (DNT) populations were within normal range: absolute α/β-TCR (T-cell receptor) DNT of 7 (normal <35 cell/µl); percentage α/β-TCR DNT of 0.5% (normal <2.0%). Systemic lupus erythematosus (SLE), Castleman’s disease, and periodic fever syndromes were considered, but no formal diagnosis was established and immune modulating medications were not yet initiated.
After multiple disease flares between the ages of 8 and 11 years which manifested as a combination of discoid malar rash, tender cervical lymphadenopathy, sub-nephrotic range proteinuria, along with serologic evidence of persistently positive ANA, anti-dsDNA, anti-ribosomal P antibodies, suppressed C3, C4, and CH50, the provisional diagnosis of systemic lupus erythematosus (SLE) was made. Hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), prednisone, and rituximab were all gradually added to control disease flares. During these years she also had persistently abnormal lung exams and was diagnosed with bronchiectasis following imaging, bronchoalveolar lavage, and a negative infectious diseases work-up. At age 11, she was hospitalized for dehydration and neutropenic fevers with an absolute neutrophil count (ANC) of 0 x 109 cells/L, anemia, and an inappropriately low reticulocyte count. Her fevers and neutropenia resolved after receiving broad spectrum antibiotics and discontinuing the MMF.
Following that hospitalization, HCQ and prednisone were continued. Over the course of the next 3 years (ages 12–14), her disease process was well controlled, and oral prednisone was gradually discontinued. During this time, her complement C3 and C4 levels were normal or elevated and anti-dsDNA antibody titers decreased, but she had progressively worsening hypogammaglobulinemia ( Figure 1 ). She began developing frequent urinary tract infections (UTIs), ear infections, and atypical pneumonia, along with cough, fevers, and conductive hearing loss with magnetic resonance imaging (MRI) findings of sinus effusions. Monthly intravenous immunoglobulin (IVIG) replacement was initiated, and her underlying diagnosis was reconsidered. Notably, repeat autoantibody testing for other connective tissue diseases, including RNP, Smith, SS-A/Ro, SS-B/La, Scleroderma, cardiolipin, as well as lupus anti-coagulant, remained negative (tested 7 times in total over ages 7-15).
Figure 1 Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.
She was referred to a genetic counselor at age 14. Parental consanguinity was noted; the patient’s maternal grandmother and paternal grandmother were sisters. A next generation sequencing (NGS) immunodeficiency panel that included over 200 genes revealed no pathogenic mutations. A repeat excisional lymph node biopsy was performed in the setting of persistent lymphadenopathy; it revealed typical reactive hyperplasia and was negative for EBV RNA by in situ hybridization (EBER-ISH) ( Figures 2 and 3 ). Whole exome sequencing identified a heterozygous de novo pathogenic variant of the TNFAIP3 gene (c. 1777 C>T in exon 7, p.Q593X); this premature stop codon is presumed to result in A20 haploinsufficiency. In the past year, (age 15), her symptoms have been well controlled with improving lymphadenopathy following escalation of therapy using prednisone, MMF, and two doses of rituximab in addition to the ongoing HCQ and monthly IVIG replacement.
Figure 2 Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.
Figure 3 Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.
Discussion
While over 24 unique TNFAIP3 mutations have been reported that are associated with autoinflammatory and autoimmune disease (reviewed in (7)), to our knowledge this is the first reported case of this particular germline mutation (c. 1777 C>T, p.Q593X) associated with HA20. The specific mutation, C>T at position c.1777 in exon 7, results in a premature stop codon that removes C-terminal Zinc Finger domains. These Zinc Finger domains on exons 4 through 7, when functional, support A20’s ubiquitin ligase activity (3). While biochemical studies have not been performed to test formally whether the mutation described in this report leads to increased TNF-α -associated NF-κB activity, there is high likelihood that this truncating mutation is pathogenic. Molecular and biochemical studies performed by Zhou, et al., who first described HA20, identified five heterozygous truncating mutations either located on an N-terminal domain proximal to the Zinc Finger domains or on the fourth Zinc Finger domain itself that resulted in reduced or no detection of A20 protein and diminished suppressive activity (5). Similar findings showing truncating mutations of most of A20 protein, the same domain as in our patient, or even only the seventh (last) Zinc Finger domain all correlated with HA20 clinical disease as well as diminished A20 expression and function in vitro (9). It is important to note that, at the time of publication, the patient described in this study has had testing showing genetic evidence of HA20 without functional biochemical assays, and therefore our diagnosis of HA20 is presumptive and not confirmed.
Whole exome sequencing of this patient and both parents also revealed that this patient’s mutation is a de novo mutation, as neither parent harbors the p.Q593X pathogenic variant. A comprehensive review of published cases by Yu and colleagues found only 10 of the 61 reported patients with inflammatory syndromes from HA20 were due to de novo mutations – the majority instead have a family history with HA20 inherited in an autosomal dominant fashion (7). Notably, initial reports characterizing extensive family pedigrees with HA20 suggest that while disease penetrance is complete, different patients with the same pathogenic mutation can express a wide range of disease phenotypes (5–8), suggesting that a combination of genetic, epigenetic, and environmental factors likely interact to produce these varied phenotypes. Also notable is that our patient’s de novo heterozygous mutation was discovered in the context of confirmed parental consanguinity, a scenario that typically raises suspicion for autosomal recessive conditions.
The initial features of HA20 in this patient included recurrent lymphadenopathy and fevers of unknown origin. In addition to persistently elevated ANA and dsDNA antibodies, by age 11 she also developed more classic features of lupus, including a discoid malar rash and sub-nephrotic range proteinuria. While there is a wide clinical spectrum of illness described in HA20, lupus-like features appear to be rare. A recent review by Yu, et al. that summarized results of 61 patients with HA20 noted that Behcet’s disease was considered as a primary diagnosis in 48% (29 of 61 patients), periodic fever syndromes in 11% (7 patients), while lupus or other connective tissue disease were only first considered in 5% (3 patients, two of whom had prominent mucosal ulcer involvement and the third with an eventual diagnosis of both autoimmune lymphoproliferative syndrome (ALPS) and HA20) (7, 8). Regardless of underlying diagnosis, mucosal ulceration remains a prominent features of HA20; Aeschlimann et al. reported all 16 patients in their cohort of HA20 patients having mucosal ulcers (8). In contrast, mucosal ulcers have not been a feature of our patient’s clinical course at any point in her life. A lack of mucosal ulcers and lupus-like phenotype are both very atypical in comparison to the reported clinical spectrum of HA20, highlighting the need to maintain clinical suspicion of HA20 even in patients without significant Behcet-like illness.
At the age of 12, the patient described in this report developed frequent UTIs, ear infections, and atypical pneumonias, associated with a progressive hypogammaglobulinemia, all of which have improved following monthly intravenous immunoglobulin (IVIG) replacement ( Figure 1 ). Notably, rituximab is a CD20 (B-cell) depleting antibody which causes hypogammaglobulinemia in a minority of patients approximately 6 months after treatment, with immunoglobulin recovery observed within the next 6-12 months following last rituximab infusion (10, 11). In contrast, our patient had last received rituximab and mycophenolate at age 10 years, with observed B-cell recovery at age 11 (as assessed by CD19, shown in Figure 1 ) 2 years prior to the onset of hypogammaglobulinemia. At age 14, she began experiencing recurrent infections with associated low immunoglobulin levels prior to the initiation of IVIG (IgG 302, normal 500-1,400 mg/dl; IgA <7, normal 47–249 mg/dl; IgM 57, normal 47–252 mg/dl). However, her absolute B-cell counts at this time remained within normal range ( Figure 1 ) and normal germinal center expansion was observed histologically ( Figure 2 ), suggesting her hypogammaglobulinemia may be intrinsically due to her disease process rather than incomplete recovery following B-cell depletion treatments. Formally, it remains unclear whether her hypogammaglobulinemia is a direct result of HA20, a consequence of her prior immunomodulatory therapy, or a combination of these factors.
While there are few reports of IgG deficiency in patients with HA20, a recent study indicated that 5 of 16 HA20 patients received IVIG, two of whom had recurrent sinopulmonary infections and a selective IgG subclass deficiency (8), though it is unclear whether these described patients’ need for IVIG was due to the HA20 disease itself or a consequence of immunosuppressive therapies. A recent genetic analysis of patients diagnosed with both chronic variable immune deficiency (CVID) and features of autoimmunity identified a truncating TNFAIP3 mutation in their cohort (12). The patient in this report has not met clinical criteria for CVID in the context of protective antibody levels detected against both tetanus and diphtheria at age 14 (pneumococcal antibody titers were not investigated) and given the uncertainty of whether her immune suppression was a primary component of her disease versus lingering medication effect. However, HA20-associated CVID is intriguing in the context of her persistently low IgG levels, low IgA, and frequent infections, and further studies are needed to more formally interrogate whether HA20 may cause a CVID-like disease with overlapping features of autoimmunity.
Cervical lymphadenopathy remains a prominent feature in this case and is atypical in comparison to other published cases. In a review of patients with HA20, only 5 of 61 patients were reported to have lymphadenopathy (7). Recently, a separate TNFAIP3 mutation was identified within a cohort of patients with ALPS (13). While ALPS was considered initially, ALPS panels conducted at age 7 and 10 both revealed normal frequencies and numbers of double-negative T-cells. Our patient’s specific p.Q593X A20 mutation has previously been reported in a MALT lymphoma (14) as well as a basal cell carcinoma (15) though both of these mutations were somatic (identified in the tumor cells) whereas our patient’s p.Q593X mutation is germline. While our patient’s lymphadenopathy was identified as typical reactive hyperplasia at age 14 ( Figure 2 ), it is unclear whether she is at higher risk for lymphoma. Additionally, independent mouse strains with B-cell specific deletion of A20 have revealed enhanced B-cell proliferation and survival but not spontaneous malignancy (16, 17). These observations suggest that HA20 alone is likely insufficient for the development of lymphoma but that it may promote tumorigenesis in the context of other oncogenes.
Conclusion
We report a novel mutation of the TNFAIP3 gene leading to haploinsufficiency of A20 (HA20). While autoinflammatory disease phenotypes are well described in HA20, persistent lymphadenopathy and hypogammaglobulinemia are atypical features. This case highlights the heterogeneity of symptoms that may occur with HA20 and illustrate that HA20 should be considered in patients in whom lupus-like disease features and immunodeficiency overlap. Given the broad role of A20 in suppressing inflammation, immune cell proliferation, and immune responses, further studies elucidating the role of HA20 in tumorigenesis and immunodeficiency should be pursued.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
ZS drafted the manuscript and prepared figures. SW prepared figures and edited the manuscript. BB oversaw clinical care of the patient and edited the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33679772 | 19,286,872 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal sepsis'. | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | DOCETAXEL, FLUOROURACIL, LEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY | 33680082 | 19,659,872 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastric perforation'. | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | DOCETAXEL, FLUOROURACIL, LEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY | 33680082 | 19,659,874 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | DOCETAXEL, FLUOROURACIL, LEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY | 33680082 | 19,659,874 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary sepsis'. | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | DOCETAXEL, FLUOROURACIL, LEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY | 33680082 | 19,657,696 | 2021 |
What was the administration route of drug 'DOCETAXEL'? | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33680082 | 19,659,874 | 2021 |
What was the administration route of drug 'FLUOROURACIL'? | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33680082 | 19,659,874 | 2021 |
What was the administration route of drug 'LEUCOVORIN CALCIUM'? | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33680082 | 19,659,874 | 2021 |
What was the administration route of drug 'OXALIPLATIN'? | Total neoadjuvant chemotherapy with FLOT scheme in resectable adenocarcinoma of the gastro-oesophageal junction or gastric adenocarcinoma: impact on pathological complete response and safety.
Gastric cancer is the fifth cause of cancer incidence worldwide. Multidisciplinary approaches that improve the survival are needed. Perioperative chemotherapies show improvement in pathological complete remission (pCR) and overall survival (OS), but less than 50% of the patients completed the chemotherapeutic regimen. The recent 5-fluorouracil, leucovorin, oxaliplatin, docetaxel-4 (FLOT4) study shows OS 50 months and pCR 16.6%, but only 46% of the patients completed pre- and postoperative treatment. This case series report evaluated pCR and safety in patients that received complete preoperative chemotherapeutic with FLOT.
Patients received eight cycles FLOT regimen before surgery. Each cycle comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-fluorouracil iv in a 24-hour infusion on day 1, every 2 weeks.
Fifty-nine patients were evaluated, 58 patients received preoperative cycles. Thirty-one patients received all eight cycles of preoperative therapy. 65.5% patients presented any major adverse event. Thirty-nine patients underwent surgery. Thirty-three biopsy reports were obtained. Six patients (18.2%) presented pCR, 13 patients (39.4%) had no lymph node involvement. OS was 21.32 months. Patients with histology of signet ring carcinoma cells had a shorter survival than other histologies.
Total neoadjuvant with FLOT chemotherapy presents an adequate safety profile, a similar pathologic regression rate, and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove total neoadjuvant chemotherapy's efficacy.
Introduction
Gastric cancer is the fifth cause of cancer incidence worldwide and the third cause of global mortality, with 1,033,701 new cases and 782,685 deaths in 2018, suggesting this cancer has a high mortality rate. Chile has one of the highest age standardised incidence rates in the world (17.8 cases per 100,000 people), surpassed only by Asian countries, and a high age standardised mortality rate (11.5 deaths per 100,000 people) when compared to the rest of the countries of the Western world [1]. There were 3,250 deaths in 2016 [2]. Multidisciplinary approaches that improve the survival of patients with gastric cancer are needed. Among them, perioperative chemotherapies seem to help in controlling the disease.
Studies evaluating perioperative chemotherapies, such as the MAGIC study (Medical Research Counsil Adjuvant Gastric Infusional Chemotherapy), in which three cycles of epirubicin, cisplatin and fluorouracil or capecitabine (ECF/ECX) were indicated before and after surgery, showed an improvement in the 5-year survival rate when compared to surgery alone, 36% versus 23% (p = 0.009), and good rates of pathologic remission after chemotherapy treatment, although only 41.6% of the patients can complete the six cycles planned [3]. In the FNCLCC/FFCD 9703 study, patients received two or three preoperative cycles of cisplatin and fluorouracil (FU) and three or four postoperative cycles of the same scheme, improving the 5-year survival rate when compared to patients underwent surgery alone, 38% versus 24% (p = 0.02), but only 22.9% of the patients completed four postoperative cycles [4]. The recent FU, leucovorin, oxaliplatin and docetaxel-4 (FLOT4) study, which uses four cycles of FLOT before and after surgery, showed a median survival of 50 months versus 35 months with the ECF/ECX scheme [5]. The complete response rate of this scheme was 16.6% [6], but only 46% of the patients completed the full pre- and postoperative treatment.
These studies show that better disease-free survival and overall survival (OS) are related to a better pathologic complete remission, and higher rates of complete remission are obtained when the number of administered chemotherapy cycles is increased, e.g. 17% of pathologic complete remission after four cycles and 20% after six cycles [7, 8].
This retrospective study evaluated the safety and the rate of pathologic complete remission of complete preoperative chemotherapy with FLOT scheme.
Methods
Study design
This trial is a retrospective study, case series report, performed at the Instituto Oncologico Fundación Arturo López Pérez (FALP), Santiago, Chile. The study was carried out according to the local institutional guidelines and was approved by the local committee. The author holds responsibility for the collection and evaluation of data.
The primary objective of the study was to determine the rate of pathological remission and the safety of patients who underwent a total neoadjuvant regimen with FLOT regimen before surgery. Other objectives were intensity of treatment received, type and complications of surgery, OS of all patients treated with preoperative chemotherapy and according histological subtype.
All patients were presented to the cancer multidisciplinary team meeting of experts in the treatment of gastric cancer who prescribed total neoadjuvant therapy with FLOT regimen between November 2016 and May 2019.
Eligible patients had gastric or gastro-oesophageal junction cancer histologically confirmed as adenocarcinomas in clinical stage T1–T4 with involvement lymph node (N+), or extensive T3N0, or T4N0. The tumours were classified according to the Tumour-Node-Metastasis (TNM) Classification of Malignant Tumours of the Union for International Cancer Control (UICC), 7th edition. The clinical stage was assigned by evaluating the physical exam, an oesophagus-stomach-duodenum endoscopy and computerised tomography scans of the thorax, abdomen and pelvis.
Procedures
Patients received eight cycles of FLOT chemotherapeutic regimen administered before surgery. Each cycle, performed every 2 weeks, comprised 50 mg/m2 docetaxel intravenous (iv) on day 1, 85 mg/m2 oxaliplatin iv on day 1, 200 mg/m2 leucovorin iv on day 1 and 2,600 mg/m2 5-FU iv in a 24-hour infusion on day 1. The doses of treatment could reduce and/or be temporarily or permanently suspended due to unacceptable toxicity, disease progression or at the physicians’ discretion.
Surgery was programmed 4 weeks after the last dose of chemotherapy. Patients underwent a gastrectomy with transhiatal distal oesophagectomy and a D2 lymphadenectomy at our institution FALP.
Patients were evaluated according to age at the time of diagnosis, histological type, body mass index (BMI), the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status, haemoglobin levels, albumin levels, number of administered cycles, dose reductions, adverse reactions, type of surgery, surgical mortality during the first 30 days, anatomopathological results after treatment and OS.
Serious adverse events were defined as any adverse events of grade 3, 4 or 5, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Pathological assessment
Archived haematoxylin and eosin-stained slides were evaluated by pathologists for accuracy of diagnosis. Formalin-fixed and paraffin-embedded tissue blocks were selected for tissue slides for immunohistochemistry. Cores of 5 mm with representative invasive tumour were analysed.
Histopathological reports included diagnosis according to World Health Organization (WHO) classification, UICC stage, presence or absence of lymphatic, vascular and perineural invasion and assessment of oral and distal resection margin and nodal involvement.
The tumours were classified adenocarcinomas: signet ring, tubular, mucinous, papillary, uncommon variants and not otherwise specified (NOS)
Statistics
GraphPad Prism version 8.0 was used for all statistical calculations. For exploratory and descriptive analysis, scale variables were determined as median (range) and ordinal or dichotomous variables as absolute and relative frequencies. Survival data was plotted and analysed according to the Kaplan–Meyer method. For statistical testing, the following methods were used: Log-rank (Mantel–Cox) test and Hazard Ratio (logrank).
The overall survival was determined as period of time from first chemotherapy to death. The dates of death were recollected by death records provided by the civil registration national office until 22 September 2019.
Results
Fifty-nine patients received the indication of total neoadjuvant chemotherapy with FLOT between November 2016 and May 2019. Patients were evaluated until 22 September 2019.
This study included 36 men and 23 women. The mean age at diagnosis was 61.4 (33–80) years in men and 58.5 (32–77) years in women. 72.9% of the patients had an ECOG 0, and none had an ECOG ≥ 2.
As for the histological typification, adenocarcinomas were NOS type in 23 patients (40%), signet ring type in 17 patients (29%), tubular carcinomas in 16 patients (27%) and mucinous carcinomas in 3 patients (5%). The histological degree, according to the WHO, was grade 2 in 29%, grade 3 in 56% and grade 4 in 5% of the patients; this information was not available for one patient (Table 1). Twenty-eight patients (53.8%) presented a stage IIB, followed by stage IIIA (17.3%) and stage IIA (13.4%) (Table 2). The initial clinical stage could not be determined in seven patients. At the time of diagnosis, 50 patients presented lymph node involvement.
Multidisciplinary oncology team prescribed complete neoadjuvant treatment with FLOT regimen to 59 patients. Fifty-eight patients received any preoperative cycles (Figure 1). The average number of cycles received was 6.41 (2–8 cycles). Forty-two patients (72.4%) received more than four cycles of chemotherapy, and 31 patients (53.4%) received eight cycles of preoperative therapy. Thirty-two patients (55.2%) required a dose reduction of the chemotherapy.
Major adverse event grade 3 or grade 4 occurred in 38 patients (67.8%). No one patient presented adverse event grade 5. Neutropenia was the most frequent complication, and occurred in 21 patients, neutropenia febrile occurred in three patients, while seven patients presented severe gastrointestinal reactions, such as diarrhoea or mucositis, six patients presented fatigue grade 3, five patients presented hyperemesis grade 3 and three patients presented deep vein thrombosis. Severe sepsis occurred in two patients; the original foci were abdomen and lung, respectively. One patient presented a gastric burst during the third cycle of chemotherapy and required surgery. There were no deaths related to therapy.
One patient was still receiving chemotherapy during the analysis of the study. Thirty-nine patients underwent surgery at FALP, and six patients did so at other institutions. Three patients were pending surgery. The data were not available for two patients. One patient presented a severe complication with a gastric burst, and one patient did not return after the third cycle of chemotherapy.
Five patients suffered progression of the disease during chemotherapy. The disease progression of these patients was evaluated by imaging and they did not underwent surgery.
Of the 39 patients that received surgery at our institution, 30 underwent total gastrectomy with D2 dissection. Four patients were subjected to a subtotal gastrectomy. Four patients only had an exploratory laparoscopy because they presented peritoneal carcinomatosis at surgery. Surgery protocol was not available in one patient (Figure 1). Other interventions performed in patients underwent gastrectomy with D2 resections were oophorectomy (one patient), resection of adrenal gland and pillar of the diaphragm (one patient), hyperthermic intraperitoneal chemotherapy (one patient), resection of a liver nodule (two patients) and a pancreatectomy (two patients). The biopsies of all these resections and interventions did not present malignant tumours.
The average number of days between the end of the chemotherapy and the surgery was 49.6 (13–201) days. The complications after surgery were a sepsis of unknown origin in one patient and haematemesis and pneumonia from aspiration in another patient. There were no deaths related to the surgical procedures during the first 30 days of follow-up.
A total of 33 biopsy reports from the patients underwent surgery were obtained. All specimens were adenocarcinomas. The number of lymph nodes of the samples examined was 42.9 (22–59) ganglia, and the average of positive lymph nodes was 5.38 (0–38).
As for the pathologic response observed in only biopsies reported, 6 patients (18.2%) presented a complete pathologic response, and 13 patients (39.4%) had no lymph node involvement and 1 patient presented liver metastasis (Table 3).
At the time of analysis, with a median follow-up time 20.57 months, 21 patients had died, 9 patients had undergone total gastrectomy with D2 dissection, and 1 patient was subjected to partial gastrectomy (Table 4).
The median OS was 21.3 months. 82% and 38% of the patients were alive after 1 and 2 years, respectively.
Patients with a histology of signet ring carcinoma cells had a shorter survival than those having other histologies: 13.32 months versus 24.46 months, p = 0.0003 (95% confidence interval (CI), 0.23 to 1.28), hazard ratio (HR) 0.24 (95% CI, 0.08 to 0.74), respectively (Figure 2).
Discussion
To the author’s knowledge, this is the first retrospective study to evaluate the administration of the chemotherapeutic FLOT scheme entirely as a preoperative treatment in patients with advanced gastric cancer. The pathologic responses and toxicities were evaluated after the administration of this chemotherapy.
The traditional FLOT scheme comprises four cycles before surgery and an additional four cycles after surgery. This study evaluates the administration of the eight cycles of chemotherapy before surgery with the purpose of achieving higher complete response rates without compromising the safety of the patients.
In comparison to the original studies [5, 6], the demographic characteristics of age are somewhat similar in both studies, and the proportion of women was higher in the present study. The percentage of patients with histology of signet ring adenocarcinoma was similar in both studies. However, there was a higher proportion of patients with cT3, cT4 and N+ in our study, indicating a more advanced presurgical stage in our patients. Another comparison was that only one patient underwent diagnostic laparoscopy before initiating the chemotherapy in comparison to 39% patients of the original study, that fact could imply a sub-staging of the disease in our group of patients before the treatment.
The percentage of patients that received the total number of eight cycles was slightly higher in our study, 53.4% versus 47% in the original study. We were not able to obtain the accumulated doses that they received, but our patients presented a modified dose in 55% of the cases, more significant than the 46% patients of the original studies [5, 6]. The continuity of the treatment and the higher number of cycles could explain this modification of doses. It was not possible to obtain information about the number of patients who used colony-stimulating factors.
Severe adverse events were more frequent in this review, reaching 67.8% in comparison to 41% in the studies [5, 6], probably due to more gastrointestinal events such as mucositis and diarrhoea than recorded in other studies. The most frequent complication was neutropenia, values of which were lower than those observed in studies of the FLOT scheme, probably owing to less monitoring and less use of stimulating factors. Other complications, such as fatigue and infections, were similar to those registered in previous studies. There was a gastric burst after the third cycle of chemotherapy did not record in other studies.
The histopathologic findings after treatment showed that the percentage of patients that reached a T1 or lower tumoural stage was similar to those obtained in earlier studies [6, 7]. However, the proportion of patients with N0 was less in our study.
The proportion of patients who reached a complete pathologic regression was 18% in our report compared to 16% in the previous FLOT study [6]. The value is almost similar; however, this percentage may be underestimated in our study because of variables such as patients with a more advanced clinical stage and the lesser use of staging techniques such as diagnostic laparoscopy. The number of cycles administered could influence the percentage of pathological response; however, a clinical trial with a similar population to pivotal FLOT studies and adequate follow-up should be necessary to determine it.
As in other studies [8], the survival is influenced by the histological type of the disease, being worse in patients carrying signet ring cells than in those with other histologies (HR 0.2423; 95%, 0.07970 to 0.7368).
This study had a small sample of patients, and a follow-up was too limited, which did not allow us to determine the final impact of the therapy on patient survival. However, many other studies have shown that patient survival is higher when the rate of pathological complete response to presurgical chemotherapy is higher.
Conclusion
In conclusion, total neoadjuvant with FLOT chemotherapy, entirely administered before surgery, presents an adequate safety profile, a similar rate of pathologic regression and a slightly higher rate of completing treatment to report in perioperative FLOT regimen studies. Nevertheless, our group of patients showed more advanced stages of the disease, and probably they were under staging due to lack of exploratory laparoscopy. These factors and an adequate median follow-up could influence the results of the report. A prospective clinical study with suitable diagnostic, staging tools and an adequate follow-up may prove the effectiveness of total neoadjuvant chemotherapy.
Funding
This work did not receive funding for the study design, the collection, analysis or interpretation of the data, or the preparation of the manuscript.
List of abbreviations
5-FU, 5-fluorouracil; C3, Cycle 3; D2, Extended lymph node dissection, entailing removal of nodes along the hepatic, left gastric, celiac and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a); ECF, Epirubicin, cisplatin, 5-FU; ECOG, Eastern Cooperative Oncology Group; ECX, Epirubicin, cisplatin, capecitabine; FALP, Instituto Oncologico Arturo Lopez Perez; FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; IV, Intravenous; OS, Overall survival; pCR, Pathological complete remission.
Figure 1. Trial profile. C3: cycle 3, FALP: Instituto oncologico Arturo Lopez Perez, FLOT: fluoruracil, leucovorin, oxaliplatin and docetaxel.
Figure 2. Kaplan–Meier estimates of OS in the signet ring cells group versus the others histologies group. HR = hazard ratio. CI = confidence interval.
Table 1. Baseline characteristics of population.
Age (years) All 61.4 (33–80)
<60 29 (49%)
60–69 18 (31%)
>70 12 (20%)
Sex
Male 36 (61%)
Female 23 (39%)
ECOG performance status
0 43 (72.9%)
1 16 (27.1%)
2 0 (0%)
Albumin (g/dL) All 3.7 (1.6–4.9)
Haemoglobin (g/dL) All 12.1 (7.4–15.5)
BMI (kg/m2) All 25.2 (15.4–39.5)
Male 25.8
Female 24.3
Histological classification
NOS 23 (40%)
Signet ring 17 (29%)
Tubular 16 (27%)
Mucinous 3 (5%)
Papillary 0 (0%)
Uncommon variants 0 (0%)
Histological degree (WHO)
G1 0 (0%)
G2 17 (29%)
G3 38 (66%)
G4 3 (5%)
Missing data 1
ECOG, Eastern Cooperative Oncology Group; G1, Grade 1; G2, Grade2; G3, Grade3; G4, Grade4; kg, Kilograms, m2, Meter square, NOS, Not otherwise specified; WHO, World Health Organization
Table 2. Pathologic stage at initial diagnosis (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (52)
IA 0 (0%)
IB 1 (1.9%)
IIA 7 (13.5%)
IIB 28 (53.8%)
IIIA 9 (17.3%)
IIIB 4 (7.7%)
IIIC 1 (1.9%)
IV 2 (3.8%)
Clinical tumour stage N = 59
cT1 1 (1.7%)
cT2 4 (6.8%)
cT3 47 (79.7%)
cT4 6 (10.2%)
cTx 1 (1.7%)
Table 3. Pathologic response after preoperative chemotherapy (according to TNM Classification of Malignant Tumours of the UICC, 7th edition).
N (33)
Complete response 6 (18.2%)
IA 1 (3.0%)
IB 4 (12.1%)
IIA 6 (18.2%)
IIB 4 (12.1%)
IIIA 5 (15.2%)
IIIB 2 (6.0%)
IIIC 4 (12.1%)
IV 1 (3.0%)
Tumour stage (ypT) N = 33
T1 8 (24.2%)
T2 8 (24.2%)
T3 12 (36.4%)
T4 5 (15.2%)
Tumour stage (ypN) N = 33
N0 13 (39.4%)
N1 9 (27.3%)
N2 5 (15.2%)
N3 6 (18.2%)
Table 4. Number of patients died according surgical procedures.
Procedures Number of death
Total gastrectomy and D2 dissection 9
Partial gastrectomy 1
Exploratory laparoscopy 3
Not surgery 3
Data missing 5
Total 21 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33680082 | 19,659,874 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'. | Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.
Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.
Introduction
Undifferentiated small-cell sarcomas are soft tissue malignancies which are characterized by small, round to ovoid cytomorphology with a high nuclear/cytoplasmic ratio. The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called ‘Ewing-like sarcomas’. Based on the discovery of novel molecular driving events, recent studies have enabled the identification of two distinct subgroups, these are, capicua transcriptional repressor (CIC)-rearranged sarcoma and BCL6 corepressor (BCOR)-rearranged sarcoma, within this previously uncharacterized group of Ewing-like sarcomas (1,2). In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability (1,3,4). On the other hand, BCOR is fused to mainly cyclin B3 (CCNB3) (5). These entities have different clinicopathological features. Of note, CIC-rearranged sarcomas are associated with an aggressive clinical course and poor prognosis compared to Ewing sarcoma (3). Median overall survival of patients with metastatic CIC-rearranged sarcoma is only 9-10 months (6,7). The efficacy of chemotherapy has not been prospectively evaluated, and no standard treatment has been established (7,8). Compared to CIC-rearranged sarcomas, BCOR-rearranged sarcomas have a much better prognosis (5,7), although no standard treatment for these tumors has been established either.
Here, we describe a case of metastatic CIC-rearranged sarcoma which developed years after chemotherapy for lymphoma that included alkylating agents and anthracycline, and was palliated with chemotherapy used for Ewing sarcoma.
Case report
The patient was a 24-year-old Japanese woman who had a past medical history of anaplastic large cell lymphoma at nine years old, treated with chemotherapy based on the ACLC99 protocol (9) and JACLS NHL-98 protocol (10), with subsequent autologous hematopoietic stem cell transplantation. These protocol regimens included cytotoxic drugs such as alkylating agents and anthracyclines. The cumulative dose of doxorubicin (DOX) was 150 mg/m2. She had been in long-term complete remission.
She was referred to our hospital after presenting with pain and swelling of the left shoulder in May 2018. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a 5 cm soft tissue mass located between the deltoid and humerus (Fig. 1A-C). Open biopsy was performed. Small round atypical cells with a high nuclear/cytoplasmic ratio grew in sheets (Fig. 2A) and formed alveolar structures with necrosis and fibrosis. Immunohistochemically, tumor cells were positive for WT-1, calretinin and ETS variant transcription factor 4 (ETV4), and focally positive for CD99 (Fig. 2B and C). Fluorescence in situ hybridization demonstrated CIC rearrangement (Fig. 2D). Based on these findings, the tumor was diagnosed as CIC-rearranged sarcoma. Detail of fusion partner did not be studied. CT scan revealed multiple nodules in the lungs, which were consistent with metastases.
The clinical course is summarized in Fig. 3A. First-line palliative chemotherapy with DOX, vincristine (VCR), and cyclophosphamide (CPA) was initiated in June 2018 (Fig. 3B). After the first cycle, the lung metastases had shrunk, but the primary lesion had not changed. The patient underwent a wide resection of the primary lesion with replacement using artificial humeral head in July 2018 to improve her quality of life. Pathological response to initial chemotherapy was poor. DOX, VCR, and CPA were restarted. At the end of the third cycle, her cumulative lifetime exposure of DOX had reached 350 mg/m2. We substituted actinomycin-D (Act-D) for DOX beginning with the fourth cycle to avoid cardiotoxicity (11). The CIC-rearranged sarcoma was well-controlled during six cycles, although adverse events occurred, including grade 3 febrile neutropenia and septic arthritis requiring debridement. Six months from the beginning of therapy, progression of the lung metastases developed (Fig. 3C).
We administered ifosfamide and etoposide as second-line treatment. We planned 1,800 mg/m2 of ifosfamide per day for five days and 100 mg/m2 of etoposide per day over the same five days every three weeks. Two cycles of IE achieved a good response in the lung metastases as seen on CT scan; this response lasted for 4 months (Fig. 3D). However, persistent grade 2 anorexia due to chemotherapy impaired her quality of life. In addition, some evidences have suggested that pulmonary metastasectomy may be associated with clinical benefit (12,13). As extrapulmonary metastases had not appeared, after careful discussion among the multidisciplinary team and the patient, we planned a pneumonectomy for pulmonary oligometastases for improvement of prognosis and quality of life with subsequent chemotherapy holiday after 5 cycles of IE. Despite rapid progression of the lung metastases, with a left pleural effusion appearing right before surgery (Fig. 3E), pneumonectomy and maximum debulking of the pleural metastases were performed. However, not all residual disease could be resected.
Following surgery, an aggressive clinical course was maintained. As rapidly progressive malignant pleural effusion developed, pleurodesis was performed. Although we started trabectedin (TRB) as third-line therapy, no clinical benefit was observed. She died one month later. Her overall survival from diagnosis was 13 months.
Discussion
No molecular-based targeted therapy or cancer immunotherapy for the treatment of CIC-rearranged sarcomas has been reported, and chemotherapy with cytotoxic agents is still generally used. The available data on treatment for metastatic CIC-rearranged sarcoma come from small retrospective studies. Because of the low incidence and variations in treatment, some cases were formerly diagnosed and treated as other sarcomas without pathognomonic molecular analysis (6,7,14). Palmerini et al reported that in first-line settings for metastatic CIC-rearranged sarcoma, response rates to a Ewing regimen and another regimen (DOX and ifosfamide, unknown regimen) were 57% (n=8/14) and 0% (n=0/4), respectively (8). In addition, neoadjuvant chemotherapy with Ewing regimen achieved pathological response in 3 of 10 localized CIC-rearranged sarcoma (6). These findings suggest that chemotherapy with the Ewing regimens seems to be effective for patients newly diagnosed with metastatic CIC-rearranged sarcoma, albeit that further studies are warranted.
IE is an effective regimen for treatment of recurrent Ewing sarcoma (15). This regimen is not widely used in treatment for advanced soft tissue sarcoma (16,17), although minimum activity has been reported in small phase 2 trial (18). IE is commonly used with DOX, VCR, and CPA (VDC-IE) for treatment of localized Ewing sarcoma based on the results of a randomized phase 3 trial, but the same trial revealed that VDC-IE did not improve the outcome for patients with metastatic disease (19). Thus, we did not use VDC-IE in our first-line palliative treatment but did use it for second-line treatment. To our knowledge, this is the first case with a response to an IE regimen without DOX for refractory CIC-rearranged sarcoma. Unfortunately, the patients showed poor prognosis regardless palliative chemotherapy. However, Ewing regimens, especially IE regimen achieved clinically meaningful disease control in this case, considering to highly aggressive clinical course after IE regimen failure.
There is no established treatment for Ewing sarcoma refractory to both DOX, VCR, and CPA and to IE. TRB, a tetrahydroisoquinoline alkaloid, showed anti-tumor activity in CIC-rearranged sarcoma in a xenograft model (4). Preclinical and clinical studies have shown that TRB has an anti-tumor effect in several translocation-related sarcomas (20-22). Therefore, we used TRB as third-line palliative therapy based on these findings, but saw no clinical benefit. Interestingly, TRB did not demonstrate sufficient activity against relapsed Ewing sarcoma in a phase 2 trial (23). Of ten evaluable patients, there were no partial responses, one case of stable disease, and nine cases of progressive disease. Based on the above, the clinical response to chemotherapy in our case was concordant with the clinical chemosensitivity of Ewing sarcoma.
Our case is the first report of secondary CIC-rearranged sarcoma. Secondary sarcoma associated with prior chemotherapy is well known. Various treatment-related factors are associated with the development of secondary sarcoma, including exposure to alkylating agents and/or anthracyclines and a history of autologous hematopoietic stem cell transplantation (24,25). Most secondary sarcoma belong to the category with non-recurring genetic aberrations, including undifferentiated pleomorphic sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (26). Ewing sarcoma accounts for only 5% of secondary sarcomas (24). However, CIC-rearranged sarcoma could have been overlooked in cases where pathognomonic molecular analysis was not performed. It is uncertain whether the clinical outcome differs between primary and secondary CIC-rearranged sarcoma. In our case, the previous treatment history restricted the use of DOX because of the patient's cumulative exposure.
In conclusion, we describe a case of metastatic CIC-rearranged sarcoma treated with palliative chemotherapy, beginning with an Ewing regimen, both VDC and IE. Our case and the best available clinical evidence suggest that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcomas, including second malignant case.
Acknowledgements
The authors would like to thank Dr. Akihiko Yoshida (Department of Diagnostic Pathology, National Cancer Center Hospital) for his important contributions to the pathological diagnosis.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, NK, HT, SM, TKo TH, MK, TKa, and HH substantial contributions to the acquisition of the data. SK and YI confirmed the authenticity of the raw data and drafted the manuscript. YFuj, YFun, MT and HM made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. TH and MK contributed pathological diagnosis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 MRI of the tumor at presentation. A 5 cm long mass is isointense on (A) T1-weighted imaging, and (B) hyperintense on T2-weighted imaging and (C) short inversion time inversion recovery imaging.
Figure 2 Small round atypical cells with a high nuclear/cytoplasmic ratio grow in sheets. (A) Hematoxylin and eosin stains. Magnification, x100. (B) Tumor cells are focally positive for CD99 and show strong and diffuse positive staining for (C) ETV4. Magnification, x40. (D) Fluorescence in situ hybridization shows the rearrangement of CIC gene. Split of green (5' part) and orange (3' part) signals. ETV4, ETS variant transcription factor 4.
Figure 3 Summary of clinical course. (A) Course of treatment including chemotherapy and surgery. (B) Baseline CT scan in June 2018 shows small bilateral nodules. (C) A period of six months after the initiation of doxorubicin, vincristine and cyclophosphamide, progression of lung metastases is observed. (D) IE achieved a partial response confirmed in April 2019. (E) Disease progression was observed in June 2019. IE, ifosfamide and etoposide; VCR, vincristine; DOX, doxorubicin; CPA, cyclophosphamide; TRB, trabectedin. | CYCLOPHOSPHAMIDE, DACTINOMYCIN, DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, TRABECTEDIN, VINCRISTINE | DrugsGivenReaction | CC BY-NC-ND | 33680459 | 19,217,525 | 2021-04 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.